Amlodipine formulations

ABSTRACT

Provided herein are stable amlodipine liquid formulations. Also provided herein are methods of using amlodipine liquid formulations for the treatment of certain diseases including hypertension and Coronary Artery Disease (CAD).

CROSS-REFERENCE

This is a continuation of U.S. application Ser. No. 17/067,396, filedOct. 9, 2020, which is a continuation of U.S. application Ser. No.16/381,575, filed Apr. 11, 2019, now U.S. Pat. No. 10,799,453, issuedOct. 13, 2020, which claims priority to U.S. Provisional Application No.62/656,188, filed Apr. 11, 2018, and the U.S. application Ser. No.17/067,396 is continuation of International Application No.PCT/U2019/027044, filed Apr. 11, 2019, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Hypertension, or high blood pressure, is a serious health issue in manycountries. According to the National Heart Blood and Lung Institute, itis thought that about 1 in 3 adults in the United States alone havehypertension. Left unchecked, hypertension is considered a substantialrisk factor for cardiovascular and other diseases including coronaryheart disease, myocardial infarction, congestive heart failure, strokeand kidney failure. Hypertension is classified as primary (essential)hypertension or secondary hypertension. Primary hypertension has noknown cause and may be related to a number of environmental, lifestyleand genetic factors such as stress, obesity, smoking, inactivity andsodium intake. Secondary hypertension can be caused by drug or surgicalinterventions or by abnormalities in the renal, cardiovascular orendocrine system.

A number of antihypertensive drugs are available for treatinghypertension. Various therapeutic classes of antihypertensive drugsinclude alpha-adrenergic blockers, beta-adrenergic blockers,calcium-channel blockers, hypotensives, mineralcorticoid antagonists,central alpha-agonists, diuretics and rennin-angiotensin-aldosteroneinhibitors which include angiotensin II receptor antagonists (ARB) andangiotensin-converting enzyme (ACE) inhibitors. Angiotensin-convertingenzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), apeptidyl dipeptidase that catalyzes angiotension I to angiotension II, apotent vasoconstrictor involved in regulating blood pressure.

Amlodipine is a calcium channel blocker. It affects the movement ofcalcium into the cells of the heart and blood vessels. As a result,amlodipine relaxes blood vessels and increases the supply of blood andoxygen to the heart while reducing its workload. The structural formulaof amlodipine is as follows:

Amlodipine is currently administered in the form of oral tablets, (e.g.,Norvasc®) or in the form of a refrigerated liquid formulation. Inaddition to the treatment of hypertension, amlodipine tablets have beenused for coronary artery disease (CAD) such as chronic stable angina,vasospastic angina, or angiographically documented coronary arterydisease in patients without heart failure or an ejection fraction<40%.

SUMMARY OF THE INVENTION

Disclosed herein is a process for preparing amlodipine benzoate, theprocess comprising: (i) providing an aqueous mixture comprising anamlodipine salt that is more soluble in aqueous media than amlodipinebenzoate; (ii) adding sodium benzoate to the aqueous mixture to form afirst mixture; and (iii) subjecting the first mixture to ultrasonicagitation thereby forming a second mixture comprising amlodipinebenzoate. In some embodiment of a process for preparing amlodipinebenzoate, the aqueous mixture further comprises a surfactant. In someembodiment of a process for preparing amlodipine benzoate, thesurfactant is polysorbate 80. In some embodiment of a process forpreparing amlodipine benzoate, the concentration of surfactant isbetween about 4 mg/ml and about 8 mg/ml. In some embodiment of a processfor preparing amlodipine benzoate, the concentration of surfactant isabout 6 mg/ml. In some embodiment of a process for preparing amlodipinebenzoate, the aqueous mixture is mixed prior to the addition of sodiumbenzoate in step (ii). In some embodiment of a process for preparingamlodipine benzoate, the amlodipine salt that is more soluble in aqueousmedia than amlodipine benzoate is amlodipine besylate. In someembodiment of a process for preparing amlodipine benzoate, theconcentration of amlodipine besylate is between about 12 mg/ml and about20 mg/ml. In some embodiment of a process for preparing amlodipinebenzoate, the concentration of amlodipine besylate is about 14 mg/ml. Insome embodiment of a process for preparing amlodipine benzoate, theconcentration of sodium benzoate is between about 40 mg/ml and about 70mg/ml. In some embodiment of a process for preparing amlodipinebenzoate, the concentration of sodium benzoate is about 50 mg/ml. Insome embodiment of a process for preparing amlodipine benzoate, thefirst mixture is mixed before being subjected to ultrasonic agitation.In some embodiment of a process for preparing amlodipine benzoate, thefirst mixture is mixed while being subjected to ultrasonic agitation. Insome embodiment of a process for preparing amlodipine benzoate, thefirst mixture is mixed after being subjected to ultrasonic agitation. Insome embodiment of a process for preparing amlodipine benzoate, themixing is performed for between about 1 minute and about 30 minutes. Insome embodiment of a process for preparing amlodipine benzoate, themixing is performed for between about 10 minutes and about 30 minutes.In some embodiment of a process for preparing amlodipine benzoate, thefrequency of the ultrasonic agitation is between about 20 kHz and about100 kHz. In some embodiment of a process for preparing amlodipinebenzoate, the frequency of the ultrasonic agitation is about 20 kHz. Insome embodiment of a process for preparing amlodipine benzoate, thefrequency of the ultrasonic agitation is about 40 kHz. In someembodiment of a process for preparing amlodipine benzoate, the durationof the ultrasonic agitation is between about 1 minute and 1 hour. Insome embodiment of a process for preparing amlodipine benzoate, theduration of the ultrasonic agitation is between about 5 minutes and 30minutes. In some embodiment of a process for preparing amlodipinebenzoate, the duration of the ultrasonic agitation is between about 5minutes and 20 minutes. In some embodiment of a process for preparingamlodipine benzoate, the duration of the ultrasonic agitation is about 5minutes. In some embodiment of a process for preparing amlodipinebenzoate, the duration of the ultrasonic agitation is about 10 minutes.In some embodiment of a process for preparing amlodipine benzoate, thetemperature of the first mixture or second mixture is not controlled. Insome embodiment of a process for preparing amlodipine benzoate, theprocess does not involve the use of any solvent other than water. Insome embodiment of a process for preparing amlodipine benzoate, thesecond mixture comprises amlodipine benzoate particles having a D50value between about 5 μm and about 20 μm. In some embodiment of aprocess for preparing amlodipine benzoate, the second mixture comprisesamlodipine benzoate particles having a D90 value between about 20 μm andabout 40 μm.

Also disclosed herein is a process for preparing an amlodipine benzoatesuspension, the process comprising: (i) providing an aqueous mixturecomprising an amlodipine salt that is more soluble in aqueous media thanamlodipine benzoate; (ii) adding sodium benzoate to the aqueous mixtureto form a first mixture; and (iii) subjecting the first mixture toultrasonic agitation thereby forming a second mixture comprisingamlodipine benzoate. In some embodiment of a process for preparing anamlodipine benzoate suspension, the aqueous mixture further comprises asurfactant. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the surfactant is polysorbate 80. In someembodiment of a process for preparing an amlodipine benzoate suspension,the concentration of surfactant is between about 4 mg/ml and about 8mg/ml. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the concentration of surfactant is about 6 mg/ml.In some embodiment of a process for preparing an amlodipine benzoatesuspension, the aqueous mixture is mixed prior to the addition of sodiumbenzoate in step (ii). In some embodiment of a process for preparing anamlodipine benzoate suspension, the amlodipine salt that is more solublein aqueous media than amlodipine benzoate is amlodipine besylate. Insome embodiment of a process for preparing an amlodipine benzoatesuspension, the concentration of amlodipine besylate is between about 12mg/ml and about 20 mg/ml. In some embodiment of a process for preparingan amlodipine benzoate suspension, the concentration of amlodipinebesylate is about 14 mg/ml. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the concentration of sodiumbenzoate is between about 40 mg/ml and about 70 mg/ml. In someembodiment of a process for preparing an amlodipine benzoate suspension,the concentration of sodium benzoate is about 50 mg/ml. In someembodiment of a process for preparing an amlodipine benzoate suspension,the first mixture is mixed before being subjected to ultrasonicagitation. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the first mixture is mixed while being subjected toultrasonic agitation. In some embodiment of a process for preparing anamlodipine benzoate suspension, the first mixture is mixed after beingsubjected to ultrasonic agitation. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the mixing is performed forbetween about 1 minute and about 30 minutes. In some embodiment of aprocess for preparing an amlodipine benzoate suspension, the mixing isperformed for between about 10 minutes and about 30 minutes. In someembodiment of a process for preparing an amlodipine benzoate suspension,the frequency of the ultrasonic agitation is between about 20 kHz andabout 100 kHz. In some embodiment of a process for preparing anamlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 20 kHz. In some embodiment of a process for preparingan amlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 40 kHz. In some embodiment of a process for preparingan amlodipine benzoate suspension, the duration of the ultrasonicagitation is between about 1 minute and 1 hour. In some embodiment of aprocess for preparing an amlodipine benzoate suspension, the duration ofthe ultrasonic agitation is between about 5 minutes and 30 minutes. Insome embodiment of a process for preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is between about 5minutes and 20 minutes. In some embodiment of a process for preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis about 5 minutes. In some embodiment of a process for preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis about 10 minutes. In some embodiment of a process for preparing anamlodipine benzoate suspension, the temperature of the first mixture orthe second mixture is not controlled. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the process does notinvolve the use of any solvent other than water. In some embodiment of aprocess for preparing an amlodipine benzoate suspension, the processfurther comprises adding the second mixture comprising amlodipinebenzoate to a third mixture comprising one or more of a buffer, apreservative, a sweetening agent, a suspension agent, an antifoamingagent, and a flavoring agent. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the process furthercomprises adding a second surfactant. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the second surfactantis added to the second mixture and/or the third mixture. In someembodiment of a process for preparing an amlodipine benzoate suspension,a second surfactant is added to the second mixture. In some embodimentof a process for preparing an amlodipine benzoate suspension, a secondsurfactant is added to the third mixture. In some embodiment of aprocess for preparing an amlodipine benzoate suspension, the secondsurfactant is polysorbate 80. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the process furthercomprises adding water quantum satis thereby forming the amlodipinebenzoate suspension. In some embodiment of a process for preparing anamlodipine benzoate suspension, the combined amount of the firstsurfactant and second surfactant is about 0.1 mg/ml to about 2 mg/ml. Insome embodiment of a process for preparing an amlodipine benzoatesuspension, the preservative is sodium benzoate, a paraben or parabensalt, or any combinations thereof. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the amount of preservativeis about 0.1 mg/ml to about 5.0 mg/ml. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the buffer comprises acitrate buffer. In some embodiment of a process for preparing anamlodipine benzoate suspension, the citrate buffer concentration isabout 3 mM. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the suspension agent comprises silicon dioxide,hydroxypropyl methylcellulose, methylcellulose, microcrystallinecellulose, polyvinylpyrrolidone, xanthan gum, magnesium aluminumsilicate, crosslinked polyacrylic acid polymers (e.g., Carbopol®), orany combinations thereof. In some embodiment of a process for preparingan amlodipine benzoate suspension, the suspension agent is silicondioxide. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the amount of silicon dioxide is about 0.1 mg/ml toabout 1.0 mg/ml. In some embodiment of a process for preparing anamlodipine benzoate suspension, the suspension agent is hydroxypropylmethylcellulose. In some embodiment of a process for preparing anamlodipine benzoate suspension, the amount of hydroxypropylmethylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodimentof a process for preparing an amlodipine benzoate suspension, thesuspension agent is a combination of silicon dioxide and hydroxypropylmethylcellulose. In some embodiment of a process for preparing anamlodipine benzoate suspension, the amount of silicon dioxide is about0.1 mg/ml to about 1.0 mg/ml and the amount of hydroxypropylmethylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodimentof a process for preparing an amlodipine benzoate suspension, theantifoaming agent is simethicone. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the amount of theantifoaming agent is about 0.1 mg/ml to about 1.0 mg/ml. In someembodiment of a process for preparing an amlodipine benzoate suspension,the sweetener is sucralose. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the final concentration ofamlodipine benzoate in the amlodipine benzoate suspension correspond toabout 0.8 mg/ml to about 1.2 mg/ml of amlodipine free base. In someembodiment of a process for preparing an amlodipine benzoate suspension,the amlodipine benzoate suspension comprises amlodipine benzoateparticles having a D50 value between about 5 μm and about 40 μm. In someembodiment of a process for preparing an amlodipine benzoate suspension,the amlodipine benzoate suspension comprises amlodipine benzoateparticles having a D90 value between about 20 μm and about 60 μm. Insome embodiment of a process for preparing an amlodipine benzoatesuspension, the pH of the amlodipine benzoate suspension is betweenabout 3 and about 8. In some embodiment of a process for preparing anamlodipine benzoate suspension, the pH is between about 4 and about 5.In some embodiment of a process for preparing an amlodipine benzoatesuspension, the pH is between about 5 and about 6. In some embodiment ofa process for preparing an amlodipine benzoate suspension, theamlodipine benzoate suspension is stable at about 25±5° C. for at least12 months. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the amlodipine benzoate suspension is stable atabout 5±5° C. for at least 12 months. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the amlodipine benzoatesuspension is stable at about 25±5° C. for at least 24 months. In someembodiment of a process for preparing an amlodipine benzoate suspension,the amlodipine benzoate suspension is stable at about 5±5° C. for atleast 24 months.

Also disclosed herein is a process for preparing an amlodipine benzoatesuspension, the process comprising: (i) providing an amlodipine besylateaqueous mixture; (ii) adding sodium benzoate to the aqueous mixture toform a first mixture; (iii) subjecting the first mixture to ultrasonicagitation thereby forming a second mixture comprising amlodipinebenzoate; and (iv) combining the second mixture with a third mixturecomprising sucralose, silicon dioxide, hydroxypropyl methylcellulose,simethicone, a citrate buffer, and optionally a flavoring agent toobtain the amlodipine benzoate suspension; the amlodipine benzoatesuspension comprising:

-   -   a) amlodipine benzoate in an amount corresponding to 1.0 mg/ml        amlodipine freebase;    -   b) about 3 mM of a citrate buffer;    -   c) about 0.2 mg/ml to about 5.0 mg/ml of sodium benzoate;    -   d) about 0.7 mg/mL sucralose;    -   e) about 0.5 mg/ml of silicon dioxide;    -   f) about 7.5 mg/ml of hydroxypropyl methylcellulose;    -   g) about 0.5 mg/ml simethicone;    -   h) about 1.0 mg/ml of polysorbate 80; and    -   i) water.

In some embodiment of a process for preparing an amlodipine benzoatesuspension, the aqueous mixture further comprises a first portion ofpolysorbate 80. In some embodiment of a process for preparing anamlodipine benzoate suspension, the concentration of polysorbate 80 inthe aqueous mixture is between about 4 mg/ml and about 8 mg/ml. In someembodiment of a process for preparing an amlodipine benzoate suspension,the concentration of polysorbate 80 is about 6 mg/ml. In some embodimentof a process for preparing an amlodipine benzoate suspension, theaqueous mixture is mixed prior to the addition of sodium benzoate instep (ii). In some embodiment of a process for preparing an amlodipinebenzoate suspension, the concentration of amlodipine besylate in theaqueous mixture is between about 12 mg/ml and about 20 mg/ml. In someembodiment of a process for preparing an amlodipine benzoate suspension,the concentration of amlodipine besylate in the aqueous mixture is about14 mg/ml. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the concentration of sodium benzoate in the firstmixture is between about 40 mg/ml and about 70 mg/ml. In some embodimentof a process for preparing an amlodipine benzoate suspension, theconcentration of sodium benzoate in the first mixture is about 50 mg/ml.In some embodiment of a process for preparing an amlodipine benzoatesuspension, the first mixture is mixed before being subjected toultrasonic agitation. In some embodiment of a process for preparing anamlodipine benzoate suspension, the first mixture is mixed while beingsubjected to ultrasonic agitation. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the first mixture is mixedafter being subjected to ultrasonic agitation. In some embodiment of aprocess for preparing an amlodipine benzoate suspension, the mixing isperformed for between about 1 minute and about 30 minutes. In someembodiment of a process for preparing an amlodipine benzoate suspension,the mixing is performed for between about 10 minutes and about 30minutes. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the frequency of the ultrasonic agitation isbetween about 20 kHz and about 100 kHz. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the frequency of theultrasonic agitation is about 20 kHz. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the frequency of theultrasonic agitation is about 40 kHz. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the duration of theultrasonic agitation is between about 1 minute and 1 hour. In someembodiment of a process for preparing an amlodipine benzoate suspension,the duration of the ultrasonic agitation is between about 5 minutes and30 minutes. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the duration of the ultrasonic agitation is betweenabout 5 minutes and 20 minutes. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the duration of theultrasonic agitation is about 5 minutes. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the duration of theultrasonic agitation is about 10 minutes. In some embodiment of aprocess for preparing an amlodipine benzoate suspension, the temperatureof the first mixture or second mixture is not controlled. In someembodiment of a process for preparing an amlodipine benzoate suspension,the process does not involve the use of any solvent other than water. Insome embodiment of a process for preparing an amlodipine benzoatesuspension, the process further comprises adding a second portion ofpolysorbate 80 to the second mixture prior to step (iv). In someembodiment of a process for preparing an amlodipine benzoate suspension,the process further comprises adding water quantum satis thereby formingthe amlodipine benzoate suspension. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the amlodipine benzoatesuspension comprises amlodipine benzoate particles having a D50 valuebetween about 5 μm and about 40 μm. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the amlodipine benzoatesuspension comprises amlodipine benzoate particles having a D90 valuebetween about 20 μm and about 60 μm. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the pH of the amlodipinebenzoate suspension is between about 3 and about 8. In some embodimentof a process for preparing an amlodipine benzoate suspension, the pH isbetween about 4 and about 5. In some embodiment of a process forpreparing an amlodipine benzoate suspension, the pH is between about 5and about 6. In some embodiment of a process for preparing an amlodipinebenzoate suspension, the amlodipine benzoate suspension is stable atabout 25±5° C. for at least 12 months. In some embodiment of a processfor preparing an amlodipine benzoate suspension, the amlodipine benzoatesuspension is stable at about 5±5° C. for at least 12 months. In someembodiment of a process for preparing an amlodipine benzoate suspension,the amlodipine benzoate suspension is stable at about 25±5° C. for atleast 24 months. In some embodiment of a process for preparing anamlodipine benzoate suspension, the amlodipine benzoate suspension isstable at about 5±5° C. for at least 24 months.

Also disclosed herein is a suspension comprising amlodipine benzoateparticles having a D50 value between about 5 μm and about 40 μm, thesuspension made by the process comprising: (i) providing an aqueousmixture of an amlodipine salt that is more soluble in aqueous media thanamlodipine benzoate; (ii) adding sodium benzoate to the aqueous mixtureto form a first mixture; and (iii) subjecting the first mixture toultrasonic agitation thereby forming a second mixture comprisingamlodipine benzoate. In some embodiment of a suspension comprisingamlodipine benzoate, the amlodipine benzoate particles have a D50 valuebetween about 10 μm and about 20 μm. In some embodiment of a suspensioncomprising amlodipine benzoate, the amlodipine benzoate particles have aD90 value between about 20 μm and about 60 μm. In some embodiment of asuspension comprising amlodipine benzoate, the aqueous mixture furthercomprises a surfactant. In some embodiment of a suspension comprisingamlodipine benzoate, the surfactant is polysorbate 80. In someembodiment of a suspension comprising amlodipine benzoate, theconcentration of surfactant is between about 4 mg/ml and about 8 mg/ml.In some embodiment of a suspension comprising amlodipine benzoate, theconcentration of surfactant is about 6 mg/ml. In some embodiment of asuspension comprising amlodipine benzoate, the aqueous mixture is mixedprior to the addition of sodium benzoate in step (ii). In someembodiment of a suspension comprising amlodipine benzoate, theamlodipine salt that is more soluble in aqueous media than amlodipinebenzoate is amlodipine besylate. In some embodiment of a suspensioncomprising amlodipine benzoate, the concentration of amlodipine besylateis between about 12 mg/ml and about 20 mg/ml. In some embodiment of asuspension comprising amlodipine benzoate, the concentration ofamlodipine besylate is about 14 mg/ml. In some embodiment of asuspension comprising amlodipine benzoate, the concentration of sodiumbenzoate is between about 40 mg/ml and about 70 mg/ml. In someembodiment of a suspension comprising amlodipine benzoate, theconcentration of sodium benzoate is about 50 mg/ml. In some embodimentof a suspension comprising amlodipine benzoate, the first mixture ismixed before being subjected to ultrasonic agitation. In some embodimentof a suspension comprising amlodipine benzoate, the first mixture ismixed while being subjected to ultrasonic agitation. In some embodimentof a suspension comprising amlodipine benzoate, the first mixture ismixed after being subjected to ultrasonic agitation. In some embodimentof a suspension comprising amlodipine benzoate, the mixing is performedfor between about 1 minute and about 30 minutes. In some embodiment of asuspension comprising amlodipine benzoate, the mixing is performed forbetween about 10 minutes and about 30 minutes. In some embodiment of asuspension comprising amlodipine benzoate, the frequency of theultrasonic agitation is between about 20 kHz and about 100 kHz. In someembodiment of a suspension comprising amlodipine benzoate, the frequencyof the ultrasonic agitation is about 20 kHz. In some embodiment of asuspension comprising amlodipine benzoate, the frequency of theultrasonic agitation is about 40 kHz. In some embodiment of a suspensioncomprising amlodipine benzoate, the duration of the ultrasonic agitationis between about 1 minute and 1 hour. In some embodiment of a suspensioncomprising amlodipine benzoate, the duration of the ultrasonic agitationis between about 5 minutes and 30 minutes. In some embodiment of asuspension comprising amlodipine benzoate, the duration of theultrasonic agitation is between about 5 minutes and 20 minutes. In someembodiment of a suspension comprising amlodipine benzoate, the durationof the ultrasonic agitation is about 5 minutes. In some embodiment of asuspension comprising amlodipine benzoate, the duration of theultrasonic agitation is about 10 minutes. In some embodiment of asuspension comprising amlodipine benzoate, the temperature of the firstmixture or the second mixture is not controlled. In some embodiment of asuspension comprising amlodipine benzoate, the process does not involvethe use of any solvent other than water. In some embodiment of asuspension comprising amlodipine benzoate, the process further comprisesadding the second mixture comprising amlodipine benzoate to a thirdmixture comprising at least one of a buffer, a preservative, asweetening agent, a suspension agent, an antifoaming agent, and aflavoring agent. In some embodiment of a suspension comprisingamlodipine benzoate, the process further comprises adding a secondsurfactant. In some embodiment of a suspension comprising amlodipinebenzoate, the second surfactant is added to the second mixture and/orthe third mixture. In some embodiment of a suspension comprisingamlodipine benzoate, the second surfactant is added to the secondmixture. In some embodiment of a suspension comprising amlodipinebenzoate, the second surfactant is added to the third mixture. In someembodiment of a suspension comprising amlodipine benzoate, the secondsurfactant is polysorbate 80. In some embodiment of a suspensioncomprising amlodipine benzoate, the process further comprises addingwater quantum satis thereby forming the amlodipine benzoate suspension.In some embodiment of a suspension comprising amlodipine benzoate, thecombined amount of the first surfactant and second surfactant is about0.1 mg/ml to about 2 mg/ml. In some embodiment of a suspensioncomprising amlodipine benzoate, the preservative is sodium benzoate, aparaben or paraben salt, or any combinations thereof. In some embodimentof a suspension comprising amlodipine benzoate, the amount ofpreservative is about 0.1 mg/ml to about 5.0 mg/ml. In some embodimentof a suspension comprising amlodipine benzoate, the buffer comprises acitrate buffer. In some embodiment of a suspension comprising amlodipinebenzoate, the citrate buffer concentration is about 3 mM. In someembodiment of a suspension comprising amlodipine benzoate, thesuspension agent comprises silicon dioxide, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose,polyvinylpyrrolidone, xanthan gum, magnesium aluminum silicate,crosslinked polyacrylic acid polymers (e.g., Carbopol®), or anycombinations thereof. In some embodiment of a suspension comprisingamlodipine benzoate, the suspension agent is silicon dioxide. In someembodiment of a suspension comprising amlodipine benzoate, the amount ofsilicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml. In someembodiment of a suspension comprising amlodipine benzoate, thesuspension agent is hydroxypropyl methylcellulose. In some embodiment ofa suspension comprising amlodipine benzoate, the amount of hydroxypropylmethylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodimentof a suspension comprising amlodipine benzoate, the suspension agent isa combination of silicon dioxide and hydroxypropyl methylcellulose. Insome embodiment of a suspension comprising amlodipine benzoate, theamount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml and theamount of hydroxypropyl methylcellulose is about 3 mg/ml to about 10mg/ml. In some embodiment of a suspension comprising amlodipinebenzoate, the antifoaming agent is simethicone. In some embodiment of asuspension comprising amlodipine benzoate, the amount of the antifoamingagent is about 0.1 mg/ml to about 1.0 mg/ml. In some embodiment of asuspension comprising amlodipine benzoate, the sweetener is sucralose.In some embodiment of a suspension comprising amlodipine benzoate, thefinal concentration of amlodipine benzoate in the amlodipine benzoatesuspension correspond to about 0.8 mg/ml to about 1.2 mg/ml ofamlodipine free base. In some embodiment of a suspension comprisingamlodipine benzoate, the pH of the amlodipine benzoate suspension isbetween about 3 and about 8. In some embodiment of a suspensioncomprising amlodipine benzoate, the pH is between about 4 and about 5.In some embodiment of a suspension comprising amlodipine benzoate, thepH is between about 5 and about 6. In some embodiment of a suspensioncomprising amlodipine benzoate, the amlodipine benzoate suspension isstable at about 25±5° C. for at least 12 months. In some embodiment of asuspension comprising amlodipine benzoate, the amlodipine benzoatesuspension is stable at about 5±5° C. for at least 12 months. In someembodiment of a suspension comprising amlodipine benzoate, theamlodipine benzoate suspension is stable at about 25±5° C. for at least24 months. In some embodiment of a suspension comprising amlodipinebenzoate, the amlodipine benzoate suspension is stable at about 5±5° C.for at least 24 months.

Also disclosed herein is a method of treating hypertension in a subjectcomprising administering to that subject a therapeutically effectiveamount of a suspension comprising amlodipine benzoate particles having aD50 value between about 5 μm and about 40 μm, the suspension made by theprocess comprising: (i) providing an aqueous mixture of an amlodipinesalt that is more soluble in aqueous media than amlodipine benzoate;(ii) adding sodium benzoate to the aqueous mixture to form a firstmixture; and (iii) subjecting the first mixture to ultrasonic agitationthereby forming a second mixture comprising amlodipine benzoate. In someembodiment of a method of treating hypertension in a subject, theamlodipine benzoate particles have a D50 value between about 10 μm andabout 20 μm. In some embodiment of a method of treating hypertension ina subject, the amlodipine benzoate particles have a D90 value betweenabout 20 μm and about 60 μm. In some embodiment of a method of treatinghypertension in a subject, the aqueous mixture further comprises asurfactant. In some embodiment of a method of treating hypertension in asubject, the surfactant is polysorbate 80. In some embodiment of amethod of treating hypertension in a subject, the concentration ofsurfactant is between about 4 mg/ml and about 8 mg/ml. In someembodiment of a method of treating hypertension in a subject, theconcentration of surfactant is about 6 mg/ml. In some embodiment of amethod of treating hypertension in a subject, the aqueous mixture ismixed prior to the addition of sodium benzoate in step (ii). In someembodiment of a method of treating hypertension in a subject, theamlodipine salt that is more soluble in aqueous media than amlodipinebenzoate is amlodipine besylate. In some embodiment of a method oftreating hypertension in a subject, the concentration of amlodipinebesylate is between about 12 mg/ml and about 20 mg/ml. In someembodiment of a method of treating hypertension in a subject, theconcentration of amlodipine besylate is about 14 mg/ml. In someembodiment of a method of treating hypertension in a subject, theconcentration of sodium benzoate is between about 40 mg/ml and about 70mg/ml. In some embodiment of a method of treating hypertension in asubject, the concentration of sodium benzoate is about 50 mg/ml. In someembodiment of a method of treating hypertension in a subject, the firstmixture is mixed before being subjected to ultrasonic agitation. In someembodiment of a method of treating hypertension in a subject, the firstmixture is mixed while being subjected to ultrasonic agitation. In someembodiment of a method of treating hypertension in a subject, the firstmixture is mixed after being subjected to ultrasonic agitation. In someembodiment of a method of treating hypertension in a subject, the mixingis performed for between about 1 minute and about 30 minutes. In someembodiment of a method of treating hypertension in a subject, the mixingis performed for between about 10 minutes and about 30 minutes. In someembodiment of a method of treating hypertension in a subject, thefrequency of the ultrasonic agitation is between about 20 kHz and about100 kHz. In some embodiment of a method of treating hypertension in asubject, the frequency of the ultrasonic agitation is about 20 kHz. Insome embodiment of a method of treating hypertension in a subject, thefrequency of the ultrasonic agitation is about 40 kHz. In someembodiment of a method of treating hypertension in a subject, theduration of the ultrasonic agitation is between about 1 minute and 1hour. In some embodiment of a method of treating hypertension in asubject, the duration of the ultrasonic agitation is between about 5minutes and 30 minutes. In some embodiment of a method of treatinghypertension in a subject, the duration of the ultrasonic agitation isbetween about 5 minutes and 20 minutes. In some embodiment of a methodof treating hypertension in a subject, the duration of the ultrasonicagitation is about 5 minutes. In some embodiment of a method of treatinghypertension in a subject, the duration of the ultrasonic agitation isabout 10 minutes. In some embodiment of a method of treatinghypertension in a subject, the temperature of the first mixture or thesecond mixture is not controlled. In some embodiment of a method oftreating hypertension in a subject, the process does not involve the useof any solvent other than water. In some embodiment of a method oftreating hypertension in a subject, the process further comprises addingthe second mixture comprising amlodipine benzoate to a third mixturecomprising at least one of a buffer, a preservative, a sweetening agent,a suspension agent, an antifoaming agent, and a flavoring agent. In someembodiment of a method of treating hypertension in a subject, theprocess further comprises adding a second surfactant. In some embodimentof a method of treating hypertension in a subject, the second surfactantis added to the second mixture and/or the third mixture. In someembodiment of a method of treating hypertension in a subject, the secondsurfactant is added to the second mixture. In some embodiment of amethod of treating hypertension in a subject, the second surfactant isadded to the third mixture. In some embodiment of a method of treatinghypertension in a subject, the second surfactant is polysorbate 80. Insome embodiment of a method of treating hypertension in a subject, theprocess further comprises adding water quantum satis thereby forming theamlodipine benzoate suspension. In some embodiment of a method oftreating hypertension in a subject, the combined amount of the firstsurfactant and second surfactant is about 0.1 mg/ml to about 2 mg/ml. Insome embodiment of a method of treating hypertension in a subject, thepreservative is sodium benzoate, a paraben or paraben salt, or anycombinations thereof. In some embodiment of a method of treatinghypertension in a subject, the amount of preservative is about 0.1 mg/mlto about 5.0 mg/ml. In some embodiment of a method of treatinghypertension in a subject, the buffer comprises a citrate buffer. Insome embodiment of a method of treating hypertension in a subject, thecitrate buffer concentration is about 3 mM. In some embodiment of amethod of treating hypertension in a subject, the suspension agentcomprises silicon dioxide, hydroxypropyl methylcellulose,methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone,xanthan gum, magnesium aluminum silicate, crosslinked polyacrylic acidpolymers (e.g., Carbopol®), or any combinations thereof. In someembodiment of a method of treating hypertension in a subject, thesuspension agent is silicon dioxide. In some embodiment of a method oftreating hypertension in a subject, the amount of silicon dioxide isabout 0.1 mg/ml to about 1.0 mg/ml. In some embodiment of a method oftreating hypertension in a subject, the suspension agent ishydroxypropyl methylcellulose. In some embodiment of a method oftreating hypertension in a subject, the amount of hydroxypropylmethylcellulose is about 3 mg/ml to about 10 mg/ml. In some embodimentof a method of treating hypertension in a subject, the suspension agentis a combination of silicon dioxide and hydroxypropyl methylcellulose.In some embodiment of a method of treating hypertension in a subject,the amount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml andthe amount of hydroxypropyl methylcellulose is about 3 mg/ml to about 10mg/ml. In some embodiment of a method of treating hypertension in asubject, the antifoaming agent is simethicone. In some embodiment of amethod of treating hypertension in a subject, the amount of theantifoaming agent is about 0.1 mg/ml to about 1.0 mg/ml. In someembodiment of a method of treating hypertension in a subject, thesweetener is sucralose. In some embodiment of a method of treatinghypertension in a subject, the final concentration of amlodipinebenzoate in the amlodipine benzoate suspension correspond to about 0.8mg/ml to about 1.2 mg/ml of amlodipine free base. In some embodiment ofa method of treating hypertension in a subject, the pH of the amlodipinebenzoate suspension is between about 3 and about 8. In some embodimentof a method of treating hypertension in a subject, the pH is betweenabout 4 and about 5. In some embodiment of a method of treatinghypertension in a subject, the pH is between about 5 and about 6. Insome embodiment of a method of treating hypertension in a subject, theamlodipine benzoate suspension is stable at about 25±5° C. for at least12 months. In some embodiment of a method of treating hypertension in asubject, the amlodipine benzoate suspension is stable at about 5±5° C.for at least 12 months. In some embodiment of a method of treatinghypertension in a subject, the amlodipine benzoate suspension is stableat about 25±5° C. for at least 24 months. In some embodiment of a methodof treating hypertension in a subject, the hypertension is primary(essential) hypertension. In some embodiment of a method of treatinghypertension in a subject, the hypertension is secondary hypertension.In some embodiment of a method of treating hypertension in a subject,the subject has blood pressure values greater than or equal to 140/90mmm Hg. In some embodiment of a method of treating hypertension in asubject, the subject is an adult. In some embodiment of a method oftreating hypertension in a subject, the subject is elderly. In someembodiment of a method of treating hypertension in a subject, thesubject is a child. In some embodiment of a method of treatinghypertension in a subject, the suspension is administered to the subjectin a fasted state. In some embodiment of a method of treatinghypertension in a subject, the suspension is administered to the subjectin a fed state. In some embodiment of a method of treating hypertensionin a subject, the suspension is further administered in combination withan agent selected from the group consisting of diuretics, beta blockers,alpha blockers, mixed alpha and beta blockers, calcium channel blockers,angiotensin II receptor antagonists, ACE inhibitors, aldosteroneantagonists, and alpha-2 agonists.

Also disclosed herein is a method of treating Coronary Artery Disease(CAD) in a subject comprising administering to that subject atherapeutically effective amount of a suspension comprising amlodipinebenzoate particles having a D50 value between about 5 μm and about 40μm, the suspension made by the process comprising: (i) providing anaqueous mixture of an amlodipine salt that is more soluble in aqueousmedia than amlodipine benzoate; (ii) adding sodium benzoate to theaqueous mixture to form a first mixture; and (iii) subjecting the firstmixture to ultrasonic agitation thereby forming a second mixturecomprising amlodipine benzoate. In some embodiment of a method oftreating Coronary Artery Disease (CAD) in a subject, the amlodipinebenzoate particles have a D50 value between about 10 μm and about 20 μm.In some embodiment of a method of treating Coronary Artery Disease (CAD)in a subject, the amlodipine benzoate particles have a D90 value betweenabout 20 μm and about 60 μm. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the aqueous mixture furthercomprises a surfactant. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the surfactant ispolysorbate 80. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the concentration of surfactant isbetween about 4 mg/ml and about 8 mg/ml. In some embodiment of a methodof treating Coronary Artery Disease (CAD) in a subject, theconcentration of surfactant is about 6 mg/ml. In some embodiment of amethod of treating Coronary Artery Disease (CAD) in a subject, theaqueous mixture is mixed prior to the addition of sodium benzoate instep (ii). In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate is amlodipine besylate. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the concentration of amlodipine besylate is between about 12mg/ml and about 20 mg/ml. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the concentration ofamlodipine besylate is about 14 mg/ml. In some embodiment of a method oftreating Coronary Artery Disease (CAD) in a subject, the concentrationof sodium benzoate is between about 40 mg/ml and about 70 mg/ml. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the concentration of sodium benzoate is about 50 mg/ml. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the first mixture is mixed before being subjected to ultrasonicagitation. In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the first mixture is mixed while beingsubjected to ultrasonic agitation. In some embodiment of a method oftreating Coronary Artery Disease (CAD) in a subject, the first mixtureis mixed after being subjected to ultrasonic agitation. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the mixing is performed for between about 1 minute and about 30minutes. In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the mixing is performed for between about 10minutes and about 30 minutes. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the frequency of theultrasonic agitation is between about 20 kHz and about 100 kHz. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the frequency of the ultrasonic agitation is about 20 kHz. Insome embodiment of a method of treating Coronary Artery Disease (CAD) ina subject, the frequency of the ultrasonic agitation is about 40 kHz. Insome embodiment of a method of treating Coronary Artery Disease (CAD) ina subject, the duration of the ultrasonic agitation is between about 1minute and 1 hour. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the duration of the ultrasonicagitation is between about 5 minutes and 30 minutes. In some embodimentof a method of treating Coronary Artery Disease (CAD) in a subject, theduration of the ultrasonic agitation is between about 5 minutes and 20minutes. In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the duration of the ultrasonic agitation isabout 5 minutes. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the duration of the ultrasonicagitation is about 10 minutes. In some embodiment of a method oftreating Coronary Artery Disease (CAD) in a subject, the temperature ofthe first mixture or the second mixture is not controlled. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the process does not involve the use of any solvent other thanwater. In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the process further comprises adding thesecond mixture comprising amlodipine benzoate to a third mixturecomprising at least one of a buffer, a preservative, a sweetening agent,a suspension agent, an antifoaming agent, water, and a flavoring agent.In some embodiments, the third mixture comprises water. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the process further comprises adding a second surfactant. Insome embodiment of a method of treating Coronary Artery Disease (CAD) ina subject, the second surfactant is added to the second mixture and/orthe third mixture. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the second surfactant is added to thesecond mixture. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the second surfactant is added to thethird mixture. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the second surfactant is polysorbate80. In some embodiment of a method of treating Coronary Artery Disease(CAD) in a subject, the process further comprises adding water quantumsatis thereby forming the amlodipine benzoate suspension. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the combined amount of the first surfactant and secondsurfactant is about 0.1 mg/ml to about 2 mg/ml. In some embodiment of amethod of treating Coronary Artery Disease (CAD) in a subject, thepreservative is sodium benzoate, a paraben or paraben salt, or anycombinations thereof. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the amount of preservativeis about 0.1 mg/ml to about 5.0 mg/ml. In some embodiment of a method oftreating Coronary Artery Disease (CAD) in a subject, the buffercomprises a citrate buffer. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the citrate bufferconcentration is about 3 mM. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the suspension agentcomprises silicon dioxide, hydroxypropyl methylcellulose,methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone,xanthan gum, magnesium aluminum silicate, crosslinked polyacrylic acidpolymers (e.g., Carbopol®), or any combinations thereof. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the suspension agent is silicon dioxide. In some embodiment ofa method of treating Coronary Artery Disease (CAD) in a subject, theamount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the suspension agent is hydroxypropyl methylcellulose. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the amount of hydroxypropyl methylcellulose is about 3 mg/ml toabout 10 mg/ml. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the suspension agent is a combinationof silicon dioxide and hydroxypropyl methylcellulose. In some embodimentof a method of treating Coronary Artery Disease (CAD) in a subject, theamount of silicon dioxide is about 0.1 mg/ml to about 1.0 mg/ml and theamount of hydroxypropyl methylcellulose is about 3 mg/ml to about 10mg/ml. In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the antifoaming agent is simethicone. Insome embodiment of a method of treating Coronary Artery Disease (CAD) ina subject, the amount of the antifoaming agent is about 0.1 mg/ml toabout 1.0 mg/ml. In some embodiment of a method of treating CoronaryArtery Disease (CAD) in a subject, the sweetener is sucralose. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the final concentration of amlodipine benzoate in theamlodipine benzoate suspension correspond to about 0.8 mg/ml to about1.2 mg/ml of amlodipine free base. In some embodiment of a method oftreating Coronary Artery Disease (CAD) in a subject, the pH of theamlodipine benzoate suspension is between about 3 and about 8. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the pH is between about 4 and about 5. In some embodiment of amethod of treating Coronary Artery Disease (CAD) in a subject, the pH isbetween about 5 and about 6. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the amlodipine benzoatesuspension is stable at about 25±5° C. for at least 12 months. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the amlodipine benzoate suspension is stable at about 5±5° C.for at least 12 months. In some embodiment of a method of treatingCoronary Artery Disease (CAD) in a subject, the amlodipine benzoatesuspension is stable at about 25±5° C. for at least 24 months. In someembodiment of a method of treating Coronary Artery Disease (CAD) in asubject, the Coronary Artery Disease (CAD) is chronic stable angina,vasospastic angina, or angiographically documented coronary arterydisease. In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the angiographically documented coronaryartery disease is in patients without heart failure or an ejectionfraction<40%. In some embodiment of a method of treating Coronary ArteryDisease (CAD) in a subject, the suspension is further administered incombination with an additional anti-anginal agent.

In one aspect, disclosed herein is a suspension comprising amlodipinebenzoate particles having a D50 value between about 5 μm and about 40μm, the suspension made by the process comprising: (i) providing anaqueous mixture of an amlodipine salt that is more soluble in aqueousmedia than amlodipine benzoate; (ii) adding sodium benzoate to theaqueous mixture to form a first mixture; and (iii) subjecting the firstmixture to ultrasonic agitation thereby forming a second mixturecomprising amlodipine benzoate. In some embodiments, the amlodipinebenzoate particles have a D50 value between about 10 μm and about 20 μm.In some embodiments, the amlodipine benzoate particles have a D90 valuebetween about 20 μm and about 60 μm. In some embodiments, the aqueousmixture further comprises a surfactant. In some embodiments, thesurfactant is polysorbate 80. In some embodiments, the aqueous mixtureis mixed prior to the addition of sodium benzoate in step (ii). In someembodiments, the amlodipine salt that is more soluble in aqueous mediathan amlodipine benzoate is amlodipine besylate. In some embodiments,the concentration of amlodipine besylate is between about 12 mg/ml andabout 20 mg/ml. In some embodiments, the concentration of sodiumbenzoate is between about 40 mg/ml and about 70 mg/ml. In someembodiments, the first mixture is mixed before, after, or while beingsubjected to ultrasonic agitation. In some embodiments, the frequency ofthe ultrasonic agitation is between about 20 kHz and about 100 kHz. Insome embodiments, the duration of the ultrasonic agitation is betweenabout 1 minute and 1 hour. In some embodiments, the duration of theultrasonic agitation is between about 5 minutes and 30 minutes. In someembodiments, the temperature of the first mixture or the second mixtureis not controlled. In some embodiments, the process does not involve theuse of any solvent other than water. In some embodiments, the processfurther comprises adding a second surfactant. In some embodiments, thesecond surfactant is polysorbate 80. In some embodiments, the combinedamount of the first surfactant and second surfactant is about 0.1 mg/mlto about 2 mg/ml. In some embodiments, the process further comprisesadding the second mixture comprising amlodipine benzoate to a thirdmixture comprising at least one of a buffer, a preservative, asweetening agent, a suspension agent, an antifoaming agent, water, and aflavoring agent. In some embodiments, the amount of preservative isabout 0.1 mg/ml to about 5.0 mg/ml. In some embodiments, the buffercomprises a citrate buffer. In some embodiments, the citrate bufferconcentration is about 3 mM. In some embodiments, the suspension agentcomprises silicon dioxide, hydroxypropyl methylcellulose,methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone,xanthan gum, magnesium aluminum silicate, crosslinked polyacrylic acidpolymers, or any combinations thereof. In some embodiments, thesuspension agent is a combination of silicon dioxide and hydroxypropylmethylcellulose. In some embodiments, the antifoaming agent issimethicone. In some embodiments, the final concentration of amlodipinebenzoate in the suspension corresponds to about 0.8 mg/ml to about 1.2mg/ml of amlodipine free base. In some embodiments, the suspension isstable at about 25±5° C. for at least 6 months. In some embodiments, thesuspension is stable at about 5±5° C. for at least 12 months.

In one aspect, disclosed herein is a suspension comprising amlodipinebenzoate particles having a D50 value between about 5 μm and about 40μm, the suspension made by the process comprising: (i) providing anaqueous mixture of an amlodipine salt that is more soluble in aqueousmedia than amlodipine benzoate; (ii) adding sodium benzoate to theaqueous mixture to form a first mixture; and (iii) subjecting the firstmixture to ultrasonic agitation thereby forming a second mixturecomprising amlodipine benzoate, wherein the suspension comprises: (a)amlodipine benzoate in an amount corresponding to about 0.8 mg/ml toabout 1.2 mg/ml of amlodipine free base; (b) a citrate buffer in anamount between about 1 mM and about 5 mM; (c) about 0.1 mg/ml to about5.0 mg/ml sodium benzoate; (d) about 0.1 mg/ml to about 1.0 mg/ml ofsilicon dioxide; (e) about 3 mg/ml to about 10 mg/ml of hydroxypropylmethylcellulose; (f) about 0.1 mg/ml to about 1.0 mg/ml of simethicone;(g) about 0.1 mg/ml to about 2 mg/ml of polysorbate 80; and (h) water.

In one aspect, disclosed herein is a suspension comprising amlodipinebenzoate particles having a D50 value between about 5 μm and about 40μm, the suspension made by the process comprising: (i) providing anaqueous mixture of an amlodipine salt that is more soluble in aqueousmedia than amlodipine benzoate; (ii) adding sodium benzoate to theaqueous mixture to form a first mixture; and (iii) subjecting the firstmixture to ultrasonic agitation thereby forming a second mixturecomprising amlodipine benzoate, wherein the suspension comprises: (a)amlodipine benzoate in an amount corresponding to about 1.0 mg/ml ofamlodipine free base; (b) about 3 mM of a citrate buffer; (c) about 0.1mg/ml to about 5.0 mg/ml sodium benzoate; (d) about 0.5 mg/ml of silicondioxide; (e) about 7.5 mg/ml of hydroxypropyl methylcellulose; (f) about0.15 mg/ml of simethicone; (g) about 1.0 mg/ml of polysorbate 80; and(h) water, wherein the suspension is stable at about 5±5° C. for atleast 12 months.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows the amount of amlodipine remaining in solution over time inthe presence of 1 (∘), 3 (●), 5 (Δ), 6 (▴), and 13.3 (▪) mg/mLpolysorbate 80.

FIG. 2 shows the amount of amlodipine remaining in solution over timewhen sonicated for 10 minutes at 25 kHz (∘) and 40 kHz (●) frequency.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are stable amlodipine liquid formulations. Theseamlodipine formulations described herein are useful for the treatment ofhypertension and coronary artery disease. The formulations areadvantageous over conventional solid dosage administration of amlodipineranging from ease of administration, accuracy of dosing, accessibilityto additional patient populations such as to children and the elderly,and an increased patient compliance to medication.

It is generally known that certain segments of the population havedifficulty ingesting and swallowing solid oral dosage forms such astablets and capsules. As many as a quarter of the total population hasthis difficulty. Often, this leads to non-compliance with therecommended medical therapy with the solid dosage forms, therebyresulting in rending the therapy ineffective. Further, solid dosageforms are not recommended for children or elderly due to increased riskin choking.

Furthermore, the dose of amlodipine to be given to children iscalculated according to the child's weight. When the calculated dose issomething other than the amount present in one or more intact soliddosage forms, the solid dosage form must be divided to provide thecorrect dose. This leads to inaccurate dosing when solid dosages forms,such as tablets, are compounded to prepare other formulations forchildren.

For amlodipine, one solution to overcoming the use of the tablet form isfor a compounding pharmacist to pulverize and crush the amlodipinetablet(s) into a powder via mortar and pestle and reconstitute thepowder in some liquid form. However, forming a amlodipine oral liquid inthis fashion has significant drawbacks including large variability inthe actual dosage, incomplete solubilizing of the amlodipine tablet inthe liquid, rapid instability, inconsistent formulation methods percompounding pharmacy, and a number of other potential issues. Thecrushed tablet liquid formulation may also be potentially unsafe due tocontamination with residual drugs and other substances from the mortarand pestle or other crushing agent.

The present embodiments described herein provide a safe and effectiveoral administration of amlodipine for the treatment of hypertension andother disorders. In particular, the embodiments provide stableamlodipine liquid formulations.

As used herein, “amlodipine” refers to amlodipine base, its salt, orsolvate or derivative or isomer or polymorph thereof. Suitable compoundsinclude the free base, the organic and inorganic salts, isomers, isomersalts, solvates, polymorphs, complexes etc. U.S. Pat. Nos. 4,572,909,4,879,303, 6,846,931 and WO2002/053134 disclose amlodipine and exemplaryamlodipine salt forms. In some embodiments, the amlodipine used in theformulations described herein is a pharmaceutically acceptableamlodipine salt. In some instances, the amlodipine salt is amlodipinebenzoate. In other instances, the amlodipine salt is in the form ofamlodipine naphthalene sulfonate.

Amlodipine Liquid Formulations

Liquid formulations include, but are not limited to, solutions (bothaqueous and nonaqueous), suspensions, emulsions, syrups, slurries,juices, elixirs, dispersions, and the like. It is envisioned thatsolution/suspensions are also included where certain componentsdescribed herein are in a solution while other components are in asuspension. In some embodiments, the liquid formulation described hereinis a suspension.

In one aspect, the amlodipine liquid formulations described hereincomprise a pharmaceutically acceptable salt of amlodipine, a buffer, apreservative, a sweetening agent, a surfactant, a suspension agent, anantifoaming agent, and optionally a flavoring agent. In one embodiment,the buffer is a citrate buffer. In one embodiment, the buffer comprisescitric acid. In some embodiments, the buffer further comprises sodiumcitrate. In one embodiment, the sweetening agent is sucralose. In oneembodiment, the sweetening agent is not maltitol. In another embodiment,the sweetening agent is not sucrose. In another embodiment, thepreservative is sodium benzoate. In one embodiment, the surfactant is apolysorbate. In some embodiments, the optional surfactant is polysorbate80. In one embodiment, the suspension agent is silicon dioxide. In someembodiments, the silicon dioxide is colloidal silicon dioxide. In someembodiments, the suspension agent is hydroxypropyl methylcellulose. Insome embodiments, the suspension agent is a combination of hydroxypropylmethylcellulose and silicon dioxide. In one embodiment, the antifoamingagent is simethicone.

Pharmaceutically Acceptable Salt of Amlodipine in the LiquidFormulations

Disclosed herein is a stable amlodipine liquid formulation. In someembodiments, the stable amlodipine liquid formulation is in the form ofa suspension. In some embodiments, the stable amlodipine liquidformulation comprises a pharmaceutically acceptable salt of amlodipinewhich is not soluble in an aqueous media.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis amlodipine nicotinate, amlodipine pamoate, amlodipine terephthalate,amlodipine 1-hydroxy-2-naphthoic acid salt, amlodipine(1S)-(+)-10-camphorsulfonic acid salt, or amlodipine 1,5-naphthalenedisulfonic acid salt. In some embodiments, the pharmaceuticallyacceptable salt of amlodipine is amlodipine benzoate or amlodipinenaphthalene sulfonate. In some embodiments, the pharmaceuticallyacceptable salt of amlodipine is amlodipine benzoate. In someembodiments, amlodipine benzoate or amlodipine naphthalene sulfonate areformed in situ. In some embodiments, amlodipine benzoate or amlodipinenaphthalene sulfonate are formed by the reaction of a pharmaceuticallyacceptable salt of amlodipine that is more soluble in aqueous media thanamlodipine benzoate or amlodipine naphthalene sulfonate with a molarexcess of a salt forming agent. In some embodiments, thepharmaceutically acceptable salt of amlodipine that is more soluble inaqueous media than amlodipine benzoate or amlodipine naphthalenesulfonate is selected from the group consisting of amlodipine besylate,amlodipine tosylate, amlodipine mesylate, amlodipine succinate,amlodipine salicylate, amlodipine maleate, amlodipine acetate, andamlodipine hydrochloride. In some embodiments, the pharmaceuticallyacceptable salt of amlodipine that is more soluble in aqueous media thanamlodipine benzoate or amlodipine naphthalene sulfonate is amlodipinebesylate.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis amlodipine benzoate and is formed in situ by the reaction of apharmaceutically acceptable salt of amlodipine that is more soluble inaqueous media than amlodipine benzoate with a benzoate salt formingagent. In some embodiments, the benzoate salt forming agent is benzoicacid, sodium benzoate, calcium benzoate, or potassium benzoate. In someembodiments, an excess of the benzoate salt forming agent is used toform the benzoate salt in situ. In some embodiments, the benzoate saltforming agent is sodium benzoate. In some embodiments, an excess ofsodium benzoate is used to form the benzoate salt in situ. In someembodiments, the amount of sodium benzoate used as the salt formingagent is about 1.0 mg/ml to about 10.0 mg/ml. In some embodiments, theamount of sodium benzoate used as the salt forming agent is about 1.0mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8mg/ml, about 1.9 mg/ml, about 2.0 mg/ml, about 2.1 mg/ml, about 2.2mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, about 3.0mg/ml, about 3.1 mg/ml, about 3.2 mg/ml, about 3.3 mg/ml, about 3.4mg/ml, about 3.5 mg/ml, about 3.6 mg/ml, about 3.7 mg/ml, about 3.8mg/ml, about 3.9 mg/ml, about 4.0 mg/ml, about 4.1 mg/ml, about 4.2mg/ml, about 4.3 mg/ml, about 4.4 mg/ml, about 4.5 mg/ml, about 4.6mg/ml, about 4.7 mg/ml, about 4.8 mg/ml, about 4.9 mg/ml, about 5.0mg/ml, about 5.1 mg/ml, about 5.2 mg/ml, about 5.3 mg/ml, about 5.4mg/ml, about 5.5 mg/ml, about 5.6 mg/ml, about 5.7 mg/ml, about 5.8mg/ml, about 5.9 mg/ml, about 6.0 mg/ml, about 6.1 mg/ml, about 6.2mg/ml, about 6.3 mg/ml, about 6.4 mg/ml, about 6.5 mg/ml, about 6.6mg/ml, about 6.7 mg/ml, about 6.8 mg/ml, about 6.9 mg/ml, about 7.0mg/ml, about 7.1 mg/ml, about 7.2 mg/ml, about 7.3 mg/ml, about 7.4mg/ml, about 7.5 mg/ml, about 7.6 mg/ml, about 7.7 mg/ml, about 7.8mg/ml, about 7.9 mg/ml, about 8.0 mg/ml, about 8.1 mg/ml, about 8.2mg/ml, about 8.3 mg/ml, about 8.4 mg/ml, about 8.5 mg/ml, about 8.6mg/ml, about 8.7 mg/ml, about 8.8 mg/ml, about 8.9 mg/ml, about 9.0mg/ml, about 9.1 mg/ml, about 9.2 mg/ml, about 9.3 mg/ml, about 9.4mg/ml, about 9.5 mg/ml, about 9.6 mg/ml, about 9.7 mg/ml, about 9.8mg/ml, about 9.9 mg/ml, or about 10.0 mg/ml.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis amlodipine naphthalene sulfonate and is formed in situ by thereaction of a pharmaceutically acceptable salt of amlodipine that ismore soluble in aqueous media than amlodipine naphthalene sulfonate witha naphthalene sulfonate salt forming agent. In some embodiments, thenaphthalene sulfonate salt forming agent is 1-naphthalene sulfonic acid,2-naphthalene sulfonic acid, sodium naphthalene-1-sulfonate, sodiumnaphthalene-2-sulfonate, or potassium naphthalene-2-sulfonate. In someembodiments, an excess of the naphthalene sulfonate salt forming agentis used to form the naphthalene sulfonate salt in situ. In someembodiments, the naphthalene sulfonate salt forming agent is sodiumnaphthalene-2-sulfonate. In some embodiments, an excess of sodiumnaphthalene-2-sulfonate is used to form the naphthalene sulfonate saltin situ. In some embodiments, the amount of sodiumnaphthalene-2-sulfonate used as the salt forming agent is about 0.5mg/ml to about 2.5 mg/ml. In some embodiments, the amount of sodiumnaphthalene-2-sulfonate used as the salt forming agent is about 0.5mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2.0 mg/ml, about 2.1mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, or about 2.5mg/ml.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis formed in situ as a concentrate and is subsequently diluted withwater to arrive at the final suspension. In some embodiments, theconcentrate is formed in about 5% of the final liquid volume. In someembodiments, the concentrate is formed in about 7.5% of the final liquidvolume. In some embodiments, the concentrate is formed in about 10% ofthe final liquid volume. In some embodiments, the concentrate is formedin about 12.5% of the final liquid volume. In some embodiments, theconcentrate is formed in about 15% of the final liquid volume. In someembodiments, the concentrate is formed in about 20% of the final liquidvolume. In some embodiments, the concentrate is formed in about 25% ofthe final liquid volume. In some embodiments, the concentrate is formedin about 30% of the final liquid volume. In some embodiments, theconcentrate is formed in about 35% of the final liquid volume. In someembodiments, the concentrate is formed in about 40% of the final liquidvolume. In some embodiments, the concentrate is formed in about 45% ofthe final liquid volume. In some embodiments, the concentrate is formedin about 50% of the final liquid volume. In some embodiments, theconcentrate is formed in about 55% of the final liquid volume. In someembodiments, the concentrate is formed in about 60% of the final liquidvolume. In some embodiments, the concentrate is formed in about 65% ofthe final liquid volume. In some embodiments, the concentrate is formedin about 70% of the final liquid volume. In some embodiments, theconcentrate is formed in about 75% of the final liquid volume. In someembodiments, the concentrate is formed in about 80% of the final liquidvolume. In some embodiments, the concentrate is formed in about 85% ofthe final liquid volume. In some embodiments, the concentrate is formedin about 90% of the final liquid volume. In some embodiments, theconcentrate is formed in about 95% of the final liquid volume.

In some embodiments, the concentration of the pharmaceuticallyacceptable salt of amlodipine, e.g.; amlodipine benzoate, in theconcentrate corresponds to between about 6 mg/ml and about 20 mg/ml ofamlodipine free base. In some embodiments, the concentration of thepharmaceutically acceptable salt of amlodipine in the concentrate isabout 6 mg/ml, about 6.5 mg/ml, about 7 mg/ml, about 7.5 mg/ml, about 8mg/ml, about 8.5 mg/ml, about 9 mg/ml, about 9.5 mg/ml, about 10 mg/ml,about 10.5 mg/ml, about 11 mg/ml, about 11.5 mg/ml, about 12 mg/ml,about 12.5 mg/ml, about 13 mg/ml, about 13.5 mg/ml, about 14 mg/ml,about 14.5 mg/ml, about 15 mg/ml, about 15.5 mg/ml, about 16 mg/ml,about 16.5 mg/ml, about 17 mg/ml, about 17.5 mg/ml, about 18 mg/ml,about 18.5 mg/ml, about 19 mg/ml, about 19.5 mg/ml, or about 20 mg/ml.In some embodiments, the concentration of the pharmaceuticallyacceptable salt of amlodipine e.g.; amlodipine benzoate, in theconcentrate corresponds to about 6.7 mg/ml of amlodipine free base. Insome embodiments, the concentration of the pharmaceutically acceptablesalt of amlodipine e.g.; amlodipine benzoate, in the concentratecorresponds to about 10 mg/ml of amlodipine free base. In someembodiments, the concentration of the pharmaceutically acceptable saltof amlodipine e.g.; amlodipine benzoate, in the concentrate correspondsto about 13.5 mg/ml of amlodipine free base. In some embodiments, theconcentration of the pharmaceutically acceptable salt of amlodipinee.g.; amlodipine benzoate, in the concentrate corresponds to about 20mg/ml of amlodipine free base.

In some embodiments, the pharmaceutically acceptable salt of amlodipineis amlodipine benzoate and is formed as a concentrate in situ by thereaction of a pharmaceutically acceptable salt of amlodipine that ismore soluble in aqueous media than amlodipine benzoate with sodiumbenzoate. In some embodiments, the amount of sodium benzoate used as thesalt forming agent is between about 30 mg/ml to about 100 mg/ml. In someembodiments, the amount of sodium benzoate used as the salt formingagent is about 40 mg/ml to about 70 mg/ml. In some embodiments, theamount of sodium benzoate used as the salt forming agent is about 30mg/ml, about 31 mg/ml, about 32 mg/ml, about 33 mg/ml, about 34 mg/ml,about 35 mg/ml, about 36 mg/ml, about 37 mg/ml, about 38 mg/ml, about 39mg/ml, 40 mg/ml, about 41 mg/ml, about 42 mg/ml, about 43 mg/ml, about44 mg/ml, about 45 mg/ml, about 46 mg/ml, about 47 mg/ml, about 48mg/ml, about 49 mg/ml, about 50 mg/ml, about 51 mg/ml, about 52 mg/ml,about 53 mg/ml, about 54 mg/ml, about 55 mg/ml, about 56 mg/ml, about 57mg/ml, about 58 mg/ml, about 59 mg/ml, about 60 mg/ml, about 61 mg/ml,about 62 mg/ml, about 63 mg/ml, about 64 mg/ml, about 65 mg/ml, about 66mg/ml, about 67 mg/ml, about 68 mg/ml, about 69 mg/ml, about 70 mg/ml,about 71 mg/ml, about 72 mg/ml, about 73 mg/ml, about 74 mg/ml, about 75mg/ml, about 76 mg/ml, about 77 mg/ml, about 78 mg/ml, about 79 mg/ml,about 80 mg/ml, about 81 mg/ml, about 82 mg/ml, about 83 mg/ml, about 84mg/ml, about 85 mg/ml, about 86 mg/ml, about 87 mg/ml, about 88 mg/ml,about 89 mg/ml, about 90 mg/ml, about 91 mg/ml, about 92 mg/ml, about 93mg/ml, about 94 mg/ml, about 95 mg/ml, about 96 mg/ml, about 97 mg/ml,about 98 mg/ml, about 99 mg/ml, or about 100 mg/ml.

In some embodiments, the final concentration of the pharmaceuticallyacceptable salt of amlodipine in the liquid formulation corresponds toabout 0.8 mg/ml to about 1.2 mg/ml of amlodipine free base. In otherembodiments, the final concentration of the pharmaceutically acceptablesalt of amlodipine in the liquid formulation correspond to about 0.8mg/ml, about 0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84mg/ml, about 0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88mg/ml, about 0.89 mg/ml, about 0.9 mg/ml, about 0.91 mg/ml, about 0.92mg/ml, about 0.93 mg/ml, about 0.94 mg/ml, about 0.95 mg/ml, about 0.96mg/ml, about 0.97 mg/ml, about 0.98 mg/ml, about 0.99 mg/ml, about 1.0mg/ml, about 1.01 mg/ml, about 1.02, mg/ml, about 1.03 mg/ml, about 1.04mg/ml, about 1.05 mg/ml, about 1.06 mg/ml, about 1.07 mg/ml, about 1.08mg/ml, about 1.09 mg/ml, about 1.1 mg/ml, about 1.11 mg/ml, about 1.12,mg/ml, about 1.13 mg/ml, about 1.14 mg/ml, about 1.15 mg/ml, about 1.16mg/ml, about 1.17 mg/ml, about 1.18 mg/ml, about 1.19 mg/ml, or about1.2 mg/ml of amlodipine free base. In some embodiments, the finalconcentration of the pharmaceutically acceptable salt of amlodipine inthe liquid formulation corresponds to about 0.9 mg/ml to about 1.1 mg/mlof amlodipine free base. In some embodiments, the final concentration ofthe pharmaceutically acceptable salt of amlodipine in the liquidformulation corresponds to about 1.0 mg/ml of amlodipine free base. Insome embodiments, the pharmaceutically acceptable salt of amlodipine isamlodipine benzoate. In some embodiments, the final concentration ofamlodipine benzoate in the liquid formulation corresponds to about 1.0mg/ml of amlodipine free base. In some embodiments, the pharmaceuticallyacceptable salt of amlodipine is amlodipine naphthalene sulfonate. Insome embodiments, the final concentration of amlodipine naphthalenesulfonate in the liquid formulation corresponds to about 1.0 mg/ml ofamlodipine free base.

In some embodiments, the amount of the pharmaceutically acceptable saltof amlodipine corresponds to about 1% w/w to about 16% w/w of the solidsin the liquid formulation. In other embodiments, the amount of thepharmaceutically acceptable salt of amlodipine correspond to about 1%w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w,about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w,about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w,about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w,about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w,about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9%w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8%w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7%w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6%w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5%w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w,about 10% w/w, about 10.1% w/w, about 10.2% w/w, about 10.3% w/w, about10.4% w/w, about 10.5% w/w, about 10.6% w/w, about 10.7% w/w, about10.8% w/w, about 10.9% w/w, about 11% w/w, about 11.1% w/w, about 11.2%w/w, about 11.3% w/w, about 11.4% w/w, about 11.5% w/w, about 11.6% w/w,about 11.7% w/w, about 11.8% w/w, about 11.9% w/w, about 12% w/w, about12.1% w/w, about 12.2% w/w, about 12.3% w/w, about 12.4% w/w, about12.5% w/w, about 12.6% w/w, about 12.7% w/w, about 12.8% w/w, about12.9% w/w, about 13% w/w, about 13.1% w/w, about 13.2% w/w, about 13.3%w/w, about 13.4% w/w, about 13.5% w/w, about 13.6% w/w, about 13.7% w/w,about 13.8% w/w, about 13.9% w/w, about 14% w/w, about 14.1% w/w, about14.2% w/w, about 14.3% w/w, about 14.4% w/w, about 14.5% w/w, about14.6% w/w, about 14.7% w/w, about 14.8% w/w, about 14.9% w/w, about 15%w/w, about 15.1% w/w, about 15.2% w/w, about 15.3% w/w, about 15.4% w/w,about 15.5% w/w, about 15.6% w/w, about 15.7% w/w, about 15.8% w/w,about 15.9% w/w, or about 16% w/w of the solids in the liquidformulation.

Sweetener in the Amlodipine Liquid Formulations

Sweeteners or sweetening agents include any compounds that provide asweet taste. This includes natural and synthetic sugars, natural andartificial sweeteners, natural extracts and any material that initiatesa sweet sensation in a subject. In some embodiments, a solid/powdersweetener is used in the liquid formulation described herein. In otherembodiments, a liquid sweetening agent is used in the liquid formulationdescribed herein.

Sweetening agents illustratively include glucose, fructose, sucrose,xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™(hydrogenated isomaltulose), lactitol, sorbitol, erythritol, trehalose,maltodextrin, polydextrose, and the like. Other sweetening agentsillustratively include glycerin, inulin, maltol, acesulfame and saltsthereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodiumcyclamate, saccharin and salts thereof, e.g., saccharin sodium orsaccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin,and the like. Sweetening agents can be used in the form of crude orrefined products such as hydrogenated starch hydrolysates, maltitolsyrup, high fructose corn syrup, etc., and as branded products, e.g.,Sweet Am™ liquid (propylene glycol, ethyl alcohol, and proprietaryartificial flavor combination, Flavors of North America), Sweet Am™powder (Product Code 918.005—maltodextrin, sorbitol, and fructosecombination and Product Code 918.010—water, propylene glycol, sorbitol,fructose, and proprietary natural and artificial flavor combination,Flavors of North America), ProSweet™ (1-10% proprietary plant/vegetableextract and 90-99% dextrose combination, Virginia Dare), Maltisweet™(maltitol solution, Ingredion), Sorbo™ (sorbitol and sorbitol/xylitolsolution, SPI Polyols), Invertose™ (high fructose corn syrup,Ingredion), Rebalance M60 and X60 (sucralose and maltodextrin, Tate andLyle), and Ora-Sweet® and Ora-Sweet-SF®, sugar containing andsugar-free, respectively flavored syrups (Paddock Laboratories, Inc.).Sweetening agents can be used singly or in combinations of two or more.Suitable concentrations of different sweetening agents can be selectedbased on published information, manufacturers' data sheets and byroutine testing.

In some embodiments, the amlodipine liquid formulation described hereincomprises a sweetening agent. In some embodiments, the sweetening agentis sucralose. In some embodiments, the sweetening agent is a combinationof sucralose and maltodextrin. In some embodiments, the sweetener is notmaltitol. In some embodiments, the sweetener is not sucrose.

In some embodiments, the sweetening agent is present in about 0.5 mg/mlto about 0.9 mg/ml in the liquid formulation. In other embodiments, thesweetening agent is present in about 0.51 mg/ml, about 0.52 mg/ml, about0.53 mg/ml, about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about0.57 mg/ml, about 0.58 mg/ml, about 0.59 mg/ml, about 0.60 mg/ml, about0.61 mg/ml, about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about0.65 mg/ml, about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about0.69 mg/ml, about 0.70 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about0.73 mg/ml, about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about0.77 mg/ml, about 0.78 mg/ml, about 0.79 mg/ml, about 0.80 mg/ml, about0.81 mg/ml, about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about0.85 mg/ml, about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about0.89 mg/ml, or about 0.90 mg/ml in the liquid formulation. In someembodiments, the sweetening agent is present in about 0.6 mg/ml to about0.8 mg/ml in the liquid formulation. In some embodiments, the sweeteningagent is sucralose and is present in about 0.7 mg/ml in the liquidformulation.

In some embodiments, the sweetening agent is present in about 1% w/w toabout 10% w/w of the solids in the liquid formulation. In someembodiments, the sweetening agent is present in about 1% w/w, about 1.1%w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w,about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2%w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w,about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w,about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w,about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w,about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w,about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9%w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8%w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7%w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6%w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10% w/w ofthe solids in the liquid formulation.

Preservative in the Amlodipine Liquid Formulations

Preservatives include anti-microbials, anti-oxidants, and agents thatenhance sterility. Exemplary preservatives include ascorbic acid,ascorbyl palmitate, BHA, BHT, citric acid, EDTA and its salts,erythorbic acid, fumaric acid, malic acid, propyl gallate, sodiumascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite,parabens (such as methylparaben, ethylparaben, propylparaben,butylparaben and their salts), benzoic acid, sodium benzoate, potassiumsorbate, vanillin, and the like.

In some embodiments, the amlodipine liquid formulation described hereincomprises a preservative.

In some embodiments, the preservative is a paraben, or a mixture ofparabens and the sweetener is a sugar (such as, but not limited toglucose, fructose, sucrose, lactose, maltose) or a sugar alcohol (suchas, but not limited to xylitol, mannitol, lactitol, maltitol, sorbitol).In some embodiments, the preservative is a paraben, or a mixture ofparabens and the sweetener is not a sugar or a sugar alcohol. In someembodiments, the preservative is sodium benzoate.

In some embodiments, the preservative is present in an amount sufficientto provide antimicrobial effectiveness to the amlodipine liquidformulation described herein. In some embodiments, the amount ofpreservative sufficient to provide antimicrobial effectiveness isbetween about 0.1 mg/ml and about 5.0 mg/ml. In other embodiments, theamount of preservative sufficient to provide antimicrobial effectivenessis about 0.1 mg/ml, about 0.25 mg/ml, about 0.5 mg/ml, about 0.75 mg/ml,about 1 mg/ml, about 1.25 mg/ml, about 1.5 mg/ml, about 1.75 mg/ml,about 2 mg/ml, about 2.25 mg/ml, about 2.5 mg/ml, about 2.75 mg/ml,about 3 mg/ml, about 3.25 mg/ml, about 3.5 mg/ml, about 3.75 mg/ml,about 4 mg/ml, about 4.25 mg/ml, about 4.5 mg/ml, about 4.75 mg/ml, orabout 5 mg/ml.

In some embodiments, the preservative is sodium benzoate and the amountof sodium benzoate sufficient to provide antimicrobial effectiveness isbetween about 0.2 mg/ml and about 1.0 mg/ml. In some embodiments, thepreservative is a paraben and the amount of paraben sufficient toprovide antimicrobial effectiveness is between about 1.0 mg/ml and about3.0 mg/ml. In some embodiments, the preservative is methyl paraben andthe amount of methyl paraben sufficient to provide antimicrobialeffectiveness is between about 1.0 mg/ml and about 2.0 mg/ml. In someembodiments, the preservative is propyl paraben and the amount of propylparaben sufficient to provide antimicrobial effectiveness is betweenabout 0.1 mg/ml and about 0.2 mg/ml.

In some embodiments, the preservative is present in about 0.5% w/w toabout 15% w/w of the solids in the liquid formulation. In otherembodiments, the preservative is present in about 0.5% w/w, about 1%w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w,about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8%w/w, about 8.5% w/w, about 9% w/w, about 9.5% w/w, about 10% w/w, about11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w,about 13.5% w/w, about 14% w/w, about 14.5% w/w, or about 15% w/w of thesolids in the liquid formulation.

Sweetener and Preservative Incompatibility

Paraben preservatives (especially methylparaben) can react with selectedsugars (glucose, fructose, sucrose, lactose, maltose) and sugar alcohols(xylitol, mannitol, lactitol, maltitol, sorbitol) to formtransesterification reaction products. This can be undesirable from aformulation and stability standpoint as the transesterification createsadditional degradants.

In some embodiments, the amlodipine liquid formulation described hereindoes not comprise a paraben preservative. In further embodiments, theamlodipine liquid formulation described herein does not comprise aparaben preservative when the formulation also comprises a sugar orsugar alcohol.

Buffers in the Amlodipine Liquid Formulations

Buffering agents maintain the pH of the liquid amlodipine formulation.Non-limiting examples of buffering agents include, but are not limitedto sodium bicarbonate, potassium bicarbonate, magnesium hydroxide,magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminumhydroxide/sodium bicarbonate co-precipitate, mixture of an amino acidand a buffer, a mixture of aluminum glycinate and a buffer, a mixture ofan acid salt of an amino acid and a buffer, and a mixture of an alkalisalt of an amino acid and a buffer. Additional buffering agents includecitric acid, sodium citrate, sodium tartrate, sodium acetate, sodiumcarbonate, phosphoric acid, sodium polyphosphate, potassiumpolyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodiumhydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate,tripotassium phosphate, sodium acetate, potassium metaphosphate,magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesiumsilicate, calcium acetate, calcium glycerophosphate, calcium chloride,calcium hydroxide, calcium lactate, calcium carbonate, calciumbicarbonate, and other calcium salts.

In some embodiments, the liquid formulation comprises a buffer. In someembodiments, the liquid formulation comprises a citrate buffer. In someembodiments, the buffer in the amlodipine liquid formulation describedherein comprises citric acid. In some embodiments, the buffer in theamlodipine liquid formulation described herein comprises citric acid andsodium citrate. In some embodiments, the sodium citrate is monosodiumcitrate. In some embodiments, the sodium citrate is disodium citrate. Insome embodiments, the sodium citrate is trisodium citrate. In someembodiments, the liquid formulation comprises a phosphate buffer. Insome embodiments, the buffer in the amlodipine liquid formulationdescribed herein comprises phosphoric acid. In some embodiments, thebuffer in the amlodipine liquid formulation described herein comprisesphosphoric acid and sodium phosphate. In some embodiments, the buffer inthe amlodipine liquid formulation described herein comprises sodiumphosphate. In some embodiments, the sodium phosphate is sodiumdihydrogen phosphate. In some embodiments, the sodium phosphate issodium hydrogen phosphate. In some embodiments, the sodium phosphate istrisodium phosphate.

In some embodiments, the pH of the amlodipine liquid formulationdescribed herein is between about 3 and about 8. In some embodiments,the pH of the amlodipine liquid formulation described herein is betweenabout 4 and about 5. In some embodiments, the pH of the amlodipineliquid formulation described herein is between about 5 and about 6. Insome embodiments, the pH of the amlodipine liquid formulation describedherein is less than about 4, less than about 4.5, less than about 5,less than about 5.5, less than about 6, less than about 6.5, less thanabout 7, less than about 7.5, or less than about 8. In some embodiments,the pH of the amlodipine liquid formulation described herein is about 3,about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3,about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6,about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9,about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about7.6, about 7.7, about 7.8, about 7.9, or about 8.

In some embodiments, the buffer concentration is between about 1 mM andabout 60 mM. In some embodiments, the buffer concentration is about 1mM, about 1.5 mM, about 2 mM, about 2.5 mM, about 3 mM, about 3.5 mM,about 4 mM, about 4.5 mM, about 5 mM, about 5.5 mM, about 6 mM, about6.5 mM, about 7 mM, about 7.5 mM, about 8 mM, about 8.5 mM, about 9 mM,about 9.5 mM, about 10 mM, about 10.5 mM, about 11 mM, about 11.5 mM,about 12 mM, about 12.5 mM, about 13 mM, about 13.5 mM, about 14 mM,about 14.5 mM, about 15 mM, about 15.5 mM, about 16 mM, about 16.5 mM,about 17 mM, about 17.5 mM, about 18 mM, about 18.5 mM, about 19 mM,about 19.5 mM, about 20 mM, about 20.5 mM, about 21 mM, about 21.5 mM,about 22 mM, about 22.5 mM, about 23 mM, about 23.5 mM, about 24 mM,about 24.5 mM, about 25 mM, about 25.5 mM, about 26 mM, about 26.5 mM,about 27 mM, about 27.5 mM, about 28 mM, about 28.5 mM, about 29 mM,about 29.5 mM, about 30 mM, about 30.5 mM, about 31 mM, about 31.5 mM,about 32 mM, about 32.5 mM, about 33 mM, about 33.5 mM, about 34 mM,about 34.5 mM, about 35 mM, about 35.5 mM, about 36 mM, about 36.5 mM,about 37 mM, about 37.5 mM, about 38 mM, about 38.5 mM, about 39 mM,about 39.5 mM, about 40 mM, about 40.5 mM, about 41 mM, about 41.5 mM,about 42 mM, about 42.5 mM, about 43 mM, about 43.5 mM, about 44 mM,about 44.5 mM, about 45 mM, about 45.5 mM, about 46 mM, about 46.5 mM,about 47 mM, about 47.5 mM, about 48 mM, about 48.5 mM, about 49 mM,about 49.5 mM, about 50 mM, about 50.5 mM, about 51 mM, about 51.5 mM,about 52 mM, about 52.5 mM, about 53 mM, about 53.5 mM, about 54 mM,about 54.5 mM, about 55 mM, about 55.5 mM, about 56 mM, about 56.5 mM,about 57 mM, about 57.5 mM, about 58 mM, about 58.5 mM, about 59 mM,about 59.5 mM, or about 60 mM. In some embodiments, the bufferconcentration is between about 1 mM and about 5 mM, or about 2 mM andabout 4 mM. In some embodiments, the buffer concentration is about 3 mM.

In some embodiments, the buffer in the amlodipine liquid formulationdescribed herein comprises citric acid. In some embodiments, citric acidis present in about 0.1 mg/ml to about 1.0 mg/ml in the liquidformulation. In other embodiments, citric acid is present in about 0.1mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml, about 0.18mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml, about 0.22mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the liquid formulation.In one embodiment, citric acid is present in about 0.31 mg/ml in theliquid formulation. In some embodiments, citric acid is present in about5.0 mg/ml to about 15 mg/ml in the liquid formulation. In otherembodiments, citric acid is present in about 5.0 mg/ml, about 5.5 mg/ml,about 6.0 mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml,about 8.0 mg/ml, about 8.5 mg/ml, about 9.0 mg/ml, about 9.5 mg/ml,about 10.0 mg/ml, about 10.5 mg/ml, about 11.0 mg/ml, about 11.5 mg/ml,about 12.0 mg/ml, about 12.5 mg/ml, about 13.0 mg/ml, about 13.5 mg/ml,about 14.0 mg/ml, about 14.5 mg/ml, or about 15.0 mg/ml in the liquidformulation.

In some embodiments, citric acid is present in about 1% w/w to about 45%w/w of the solids in the liquid formulation. In other embodiments,citric acid is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w,about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w,about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w,about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9%w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8%w/w, about 4.9% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8%w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w,about 18% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22%w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about27% w/w, about 28% w/w, about 29% w/w, about 30% w/w, about 31% w/w,about 32% w/w, about 33% w/w, about 34% w/w, about 35% w/w, about 36%w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, or about 45% w/wof the solids in the liquid formulation. In some embodiments, citricacid is present in about 1% w/w to about 20% w/w of the solids in theliquid formulation. In some embodiments, citric acid is present in about1% w/w to about 1.5% w/w of the solids in the liquid formulation.

In some embodiments, the amlodipine liquid formulation further comprisessodium citrate. In some embodiments, sodium citrate is present in about0.1 mg/ml to about 1.0 mg/ml in the liquid formulation. In otherembodiments, sodium citrate is present in the liquid formulation isabout 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml,about 0.14 mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml,about 0.18 mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml,about 0.22 mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml,about 0.26 mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml,about 0.3 mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml,about 0.34 mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml,about 0.38 mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml,about 0.42 mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml,about 0.46 mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml,about 0.5 mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml,about 0.54 mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml,about 0.58 mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml,about 0.62 mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml,about 0.66 mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml,about 0.7 mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml,about 0.74 mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml,about 0.78 mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml,about 0.82 mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml,about 0.86 mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml,about 0.9 mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml,about 0.94 mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml,about 0.98 mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the liquidformulation. In one embodiment, sodium citrate is present in about 0.36mg/ml in the liquid formulation.

In some embodiments, sodium citrate is present in about 1% w/w to about20% w/w of the solids in the liquid formulation. In other embodiments,sodium citrate is present in about 1% w/w, about 1.1% w/w, about 1.2%w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w,about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1%w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w,about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3%w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w,about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w,about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about4.8% w/w, about 4.9% w/w, about 5% w/w, about 6% w/w, about 7% w/w,about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w,about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17%w/w, about 18% w/w, about 19% w/w, or about 20% w/w of the solids in theliquid formulation. In some embodiments, sodium citrate is present inabout 1% w/w to about 2% w/w of the solids in the liquid formulation.

In other embodiments, sodium citrate is not added to the formulation.

In some embodiments, the buffer in the amlodipine liquid formulationdescribed herein comprises phosphoric acid. In some embodiments,phosphoric acid is present in about 0.1 mg/ml to about 2.0 mg/ml in theliquid formulation. In other embodiments, phosphoric acid is present inabout 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml,about 0.3 mg/ml, about 0.35 mg/ml, 0.4 mg/ml, about 0.45 mg/ml, about0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about0.9 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.1 mg/ml, about1.15 mg/ml, about 1.2 mg/ml, about 1.25 mg/ml, about 1.3 mg/ml, about1.35 mg/ml, about 1.4 mg/ml, about 1.45 mg/ml, about 1.5 mg/ml, about1.55 mg/ml, about 1.6 mg/mL, about 1.65 mg/mL, about 1.7 mg/ml, about1.75 mg/ml, about 1.8 mg/ml, about 1.85 mg/ml, about 1.9 mg/ml, about1.95 mg/ml, or about 2.0 mg/ml in the liquid formulation.

In some embodiments, phosphoric acid is present in about 1% w/w to about10% w/w of the solids in the liquid formulation. In other embodiments,citric acid is present in about 1% w/w, about 1.1% w/w, about 1.2% w/w,about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w,about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w,about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9%w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8%w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7%w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6%w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5%w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w,about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4%w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w,about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3%w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w,about 9.8% w/w, about 9.9% w/w, or about 10% w/w of the solids in theliquid formulation.

In some embodiments, the buffer in the amlodipine liquid formulationdescribed herein comprises sodium hydrogen phosphate. In someembodiments, sodium hydrogen phosphate is present in about 0.1 mg/ml toabout 1.0 mg/ml in the liquid formulation. In other embodiments, sodiumhydrogen phosphate is present in the liquid formulation is about 0.1mg/mL, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14mg/ml, about 0.15 mg/ml, about 0.16 mg/ml, about 0.17 mg/ml, about 0.18mg/ml, about 0.19 mg/ml, about 0.2 mg/ml, about 0.21 mg/ml, about 0.22mg/ml, about 0.23 mg/ml, about 0.24 mg/ml, about 0.25 mg/ml, about 0.26mg/ml, about 0.27 mg/ml, about 0.28 mg/ml, about 0.29 mg/ml, about 0.3mg/ml, about 0.31 mg/ml, about 0.32 mg/ml, about 0.33 mg/ml, about 0.34mg/ml, about 0.35 mg/ml, about 0.36 mg/ml, about 0.37 mg/ml, about 0.38mg/ml, about 0.39 mg/ml, about 0.4 mg/ml, about 0.41 mg/ml, about 0.42mg/ml, about 0.43 mg/ml, about 0.44 mg/ml, about 0.45 mg/ml, about 0.46mg/ml, about 0.47 mg/ml, about 0.48 mg/ml, about 0.49 mg/ml, about 0.5mg/ml, about 0.51 mg/ml, about 0.52 mg/ml, about 0.53 mg/ml, about 0.54mg/ml, about 0.55 mg/ml, about 0.56 mg/ml, about 0.57 mg/ml, about 0.58mg/ml, about 0.59 mg/ml, about 0.6 mg/ml, about 0.61 mg/ml, about 0.62mg/ml, about 0.63 mg/ml, about 0.64 mg/ml, about 0.65 mg/ml, about 0.66mg/ml, about 0.67 mg/ml, about 0.68 mg/ml, about 0.69 mg/ml, about 0.7mg/ml, about 0.71 mg/ml, about 0.72 mg/ml, about 0.73 mg/ml, about 0.74mg/ml, about 0.75 mg/ml, about 0.76 mg/ml, about 0.77 mg/ml, about 0.78mg/ml, about 0.79 mg/ml, about 0.8 mg/ml, about 0.81 mg/ml, about 0.82mg/ml, about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86mg/ml, about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9mg/ml, about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94mg/ml, about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98mg/ml, about 0.99 mg/ml, or about 1.0 mg/ml in the liquid formulation.

In some embodiments, sodium hydrogen phosphate is present in about 0.5%w/w to about 5% w/w of the solids in the liquid formulation. In otherembodiments, sodium hydrogen phosphate is present in about 0.5% w/w,about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1%w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w,about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w,about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w,about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w,about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5%w/w of the solids in the liquid formulation.

Suspension Agent in the Amlodipine Liquid Formulations

A suspension agent or dispersion agent is used to prevent the settlingof the pharmaceutically acceptable salt of amlodipine in the liquidformulation.

Suitable suspension agents include but are not limited to polymers suchas 3-butoxy-2-hydroxypropylhydroxyethylcellulose, acrylamide homo- andcopolymers, acrylic acid homo- and copolymer, alginates,carboxymethylcellulose (sodium and other salts),carboxymethylhydroxyethylcellulose, carboxy-vinyl copolymers, cellulose,such as microcrystalline cellulose, combinations of microcrystallinecellulose with carboxymethylcellulose sodium (such as Avicel® RC-501,RC-581, RC-591, and CL-611), hydrophobically modifiedhydroxyethylcellulose, hydroxyethylcellulose, hydroxypropyl guar,hydroxypropyl methylcellulose (such as Benecel K750 ® or BenecelK1500®), hydroxypropylcellulose, methylcellulose, natural gums and theirderivatives, xanthan gum, guar gum, gum Arabic, partially and fullyhydrolyzed polyvinyl alcohols, partially neutralized polyacrylic acid,polyalkylene glycol, polysaccharide gums, polyvinylpyrrolidone andderivatives thereof, starch and its derivatives, vinylpyrrolidone homo-and copolymers, water-soluble cellulose ethers, and the mixturesthereof. Other suitable suspension agents include silicon dioxide,silica powder prepared by precipitating water glass (sodium silicate)with sulfuric acid, which is then dried and sold as a fine powder, fumedalumina (made of primary particles which sinter together to formaggregates), clays such as bentonite, laponites, kaolinite, dickite, andnacrite, pyrophylite, talc, vermiculite, sauconite, saponte, nontronite,and montmorillonite, and organically modified montmorillonite clays. Insome embodiments, the suspension agent comprises silicon dioxide. Insome embodiment, the silicon dioxide is colloidal silicon dioxide.

In some embodiments, the amlodipine liquid formulation described hereincomprises a suspension agent. In some embodiments, the suspension agentcomprises silicon dioxide, hydroxypropyl methylcellulose,methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, orcombinations thereof. In some embodiments, the suspension agent issilicon dioxide. In some embodiments, the suspension agent ishydroxypropyl methylcellulose. In some embodiments, the suspension agentis a combination of silicon dioxide and hydroxypropyl methylcellulose.In some embodiments, the suspension agent is polyvinylpyrrolidone.

In some embodiments, the suspension agent is present in about 0.1 mg/mlto about 1.0 mg/ml in the liquid formulation. In other embodiments, thesuspension agent is present in about 0.1 mg/ml, about 0.15 mg/ml, about0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, or about1.0 mg/ml in the liquid formulation. In some embodiments, the suspensionagent is present in about 0.3 mg/ml to about 0.7 mg/ml in the liquidformulation. In some embodiments, the suspension agent is present inabout 0.4 mg/ml to about 0.6 mg/ml in the liquid formulation. In someembodiments, the suspension agent is silicon dioxide and is present inabout 0.5 mg/ml in the liquid formulation.

In some embodiments, the suspension agent is present in about 3.0 mg/mlto about 10.0 mg/ml in the liquid formulation. In other embodiments, thesuspension agent is present in about 3.0 mg/ml, about 3.1 mg/ml, about3.2 mg/ml, about 3.3 mg/ml, about 3.4 mg/ml, about 3.5 mg/ml, about 3.6mg/ml, about 3.7 mg/ml, about 3.8 mg/ml, about 3.9 mg/ml, about 4.0mg/ml, about 4.1 mg/ml, about 4.2 mg/ml, about 4.3 mg/ml, about 4.4mg/ml, about 4.5 mg/ml, about 4.6 mg/ml, about 4.7 mg/ml, about 4.8mg/ml, about 4.9 mg/ml, about 5.0 mg/ml, about 5.1 mg/ml, about 5.2mg/ml, about 5.3 mg/ml, about 5.4 mg/ml, about 5.5 mg/ml, about 5.6mg/ml, about 5.7 mg/ml, about 5.8 mg/ml, about 5.9 mg/ml, about 6.0mg/ml, about 6.1 mg/ml, about 6.2 mg/ml, about 6.3 mg/ml, about 6.4mg/ml, about 6.5 mg/ml, about 6.6 mg/ml, about 6.7 mg/ml, about 6.8mg/ml, about 6.9 mg/ml, about 7.0 mg/ml, about 7.1 mg/ml, about 7.2mg/ml, about 7.3 mg/ml, about 7.4 mg/ml, about 7.5 mg/ml, about 7.6mg/ml, about 7.7 mg/ml, about 7.8 mg/ml, about 7.9 mg/ml, about 8.0mg/ml, about 8.1 mg/ml, about 8.2 mg/ml, about 8.3 mg/ml, about 8.4mg/ml, about 8.5 mg/ml, about 8.6 mg/ml, about 8.7 mg/ml, about 8.8mg/ml, about 8.9 mg/ml, about 9.0 mg/ml, about 9.1 mg/ml, about 9.2mg/ml, about 9.3 mg/ml, about 9.4 mg/ml, about 9.5 mg/ml, about 9.6mg/ml, about 9.7 mg/ml, about 9.8 mg/ml, about 9.9 mg/ml, or about 10.0mg/ml in the liquid formulation. In some embodiments, the suspensionagent is present in about 4.0 mg/ml to about 6.0 mg/ml in the liquidformulation. In some embodiments, the suspension agent is present inabout 6.0 mg/ml to about 8.0 mg/ml in the liquid formulation. In someembodiments, the suspension agent is hydroxypropyl methylcellulose andis present in about 5.0 mg/ml in the liquid formulation. In someembodiments, the suspension agent is hydroxypropyl methylcellulose andis present in about 7.5 mg/ml in the liquid formulation. In someembodiments, the suspension agent is hydroxypropyl methylcellulose andis present in about 10 mg/ml in the liquid formulation.

In some embodiments, the suspension agent is present in about 10 mg/mlto about 30 mg/ml in the liquid formulation. In other embodiments, thesuspension agent is present in about 10 mg/ml, about 11 mg/ml, about 12mg/ml, about 13 mg/ml, about 14 mg/ml, about 15 mg/ml, about 16 mg/ml,about 17 mg/ml, about 18 mg/ml, about 19 mg/ml, about 20 mg/ml, about 21mg/ml, about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 mg/ml,about 26 mg/ml, about 27 mg/ml, about 28 mg/ml, about 29 mg/ml, or about30 mg/ml in the liquid formulation. In some embodiments, the suspensionagent is polyvinylpyrrolidone and is present in about 10 mg/ml in theliquid formulation. In some embodiments, the suspension agent ispolyvinylpyrrolidone and is present in about 20 mg/ml in the liquidformulation. In some embodiments, the suspension agent ispolyvinylpyrrolidone and is present in about 30 mg/ml in the liquidformulation.

In some embodiments, the suspension agent is present in about 5 mg/ml toabout 15 mg/ml in the liquid formulation. In other embodiments, thesuspension agent is present in about 5.0 mg/ml, about 5.5 mg/ml, about6.0 mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8mg/ml, about 8.5 mg/ml, about 9 mg/ml, about 9.5 mg/ml, about 10 mg/ml,about 10.5 mg/ml, about 11 mg/ml, about 11.5 mg/ml, about 12 mg/ml,about 12.5 mg/ml, about 13 mg/ml, about 13.5 mg/ml, about 14 mg/ml,about 14.5 mg/ml, or about 15 mg/ml in the liquid formulation. In someembodiments, the suspension agent is Avicel® RC-591 and is present inabout 5 mg/ml in the liquid formulation. In some embodiments, thesuspension agent is Avicel® RC-591 and is present in about 7.5 mg/ml inthe liquid formulation. In some embodiments, the suspension agent isAvicel® RC-591 and is present in about 10 mg/ml in the liquidformulation. In some embodiments, the suspension agent is Avicel® RC-591and is present in about 15 mg/ml in the liquid formulation.

In some embodiments, the suspension agent is present in about 0.4% w/wto about 6% w/w of the solids in the liquid formulation. In otherembodiments, the suspension agent is present in about 0.4% w/w, about0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9%w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8%w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7%w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6%w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5%w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w,about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4%w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w,about 5.9% w/w, or about 6% w/w of the solids in the liquid formulation.

In some embodiments, the suspension agent is present in about 20% w/w toabout 50% w/w of the solids in the liquid formulation. In otherembodiments, the suspension agent is present in about 20% w/w, about20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5%w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w,about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w,about 29.5% w/w, about 30% w/w, about 30.5% w/w, about 31% w/w, about31.5% w/w, about 32% w/w, about 32.5% w/w, about 33% w/w, about 33.5%w/w, about 34% w/w, about 34.5% w/w, about 35% w/w, about 35.5% w/w,about 36% w/w, about 36.5% w/w, about 37% w/w, about 37.5% w/w, about38% w/w, about 38.5% w/w, about 39% w/w, about 39.5% w/w, about 40% w/w,about 41% w/w, about 41.5% w/w, about 42% w/w, about 42.5% w/w, about43% w/w, about 43.5% w/w, about 44% w/w, about 44.5% w/w, about 45% w/w,about 45.5% w/w, about 46% w/w, about 46.5% w/w, about 47% w/w, about47.5% w/w, about 48% w/w, about 48.5% w/w, about 49% w/w, about 39.5%w/w, or about 50% w/w of the solids in the liquid formulation.

In some embodiments, the suspension agent is present in about 40% w/w toabout 85% w/w of the solids in the liquid formulation. In otherembodiments, the suspension agent is present in about 40% w/w, about 41%w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w, about46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w,about 51% w/w, about 52% w/w, about 53% w/w, about 54% w/w, about 55%w/w, about 56% w/w, about 57% w/w, about 58% w/w, about 59% w/w, about60% w/w, about 61% w/w, about 62% w/w, about 63% w/w, about 64% w/w,about 65% w/w, about 66% w/w, about 67% w/w, about 68% w/w, about 69%w/w, about 70% w/w, about 71% w/w, about 72% w/w, about 73% w/w, about74% w/w, about 75% w/w, about 76% w/w, about 77% w/w, about 78% w/w,about 79% w/w, about 80% w/w, about 81% w/w, about 82% w/w, about 83%w/w, about 84% w/w, or about 85% w/w of the solids in the liquidformulation.

In some embodiments, the suspension agent is present in about 35% w/w toabout 55% w/w of the solids in the liquid formulation. In otherembodiments, the suspension agent is present in about 35% w/w, about 36%w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w,about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50%w/w, about 51% w/w, about 52% w/w, about 53% w/w, about 54% w/w, orabout 55% w/w of the solids in the liquid formulation.

Antifoaming Agent in the Amlodipine Liquid Formulations

Antifoaming agents are chemical additives that reduce and hinder theformation of foam in the preparation of liquid formulations. The termsantifoaming agent and defoamer are often used interchangeably. Commonlyused agents are insoluble oils, polydimethylsiloxanes (e.g.,simethicone) and other silicones, certain alcohols, stearates andglycols. Simethicone is available as a pure material (100%) and incombination with other excipients to facilitate dispersion and handling.Common simethicone containing products include NuSil MED-342 (30% w/wsimethicone, solid), NuSil Med-340, Med-346, and Med-347 (100%simethicone, liquid), Dow Corning® Q7-2587, 7-9245, and Medical AntifoamC (30% Simethicone Emulsion). The additive is used to prevent formationof foam or is added to break foam already formed. Antifoaming agentsreduce foaming in the preparation of liquid formulations which canresult in coagulation of aqueous dispersions.

In some embodiments, the amlodipine liquid formulation described hereincomprises an antifoaming agent. In some embodiments, the antifoamingagent is simethicone.

In some embodiments, the antifoaming agent is present in about 0.05mg/ml to about 1.0 mg/ml in the liquid formulation. In some embodiments,the antifoaming agent is present in about 0.05 mg/ml to about 2.0 mg/mlin the liquid formulation. In some embodiments, the antifoaming agent ispresent in about 0.05 mg/ml to about 2.5 mg/ml in the liquidformulation. In other embodiments, the antifoaming agent is present inabout 0.05 mg/ml, about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml,about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml,about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml,about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml,about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml,about 1.1 mg/ml, about 1.15 mg/ml, about 1.2 mg/ml, about 1.25 mg/ml,about 1.3 mg/ml, about 1.35 mg/ml, about 1.4 mg/ml, about 1.45 mg/ml,about 1.5 mg/ml, about 1.55 mg/ml, about 1.6 mg/ml, about 1.65 mg/ml,about 1.7 mg/ml, about 1.75 mg/ml, about 1.8 mg/ml, about 1.85 mg/ml,about 1.9 mg/ml, about 1.95 mg/ml, about 2.0 mg/ml, about 2.05 mg/ml,about 2.1 mg/ml, about 2.15 mg/ml, about 2.2 mg/ml, about 2.25 mg/ml,about 2.3 mg/ml, about 2.35 mg/ml, about 2.4 mg/ml, about 2.45 mg/ml, orabout 2.5 mg/ml in the liquid formulation. In other embodiments, theantifoaming agent is present in about 0.6 mg/ml in the liquidformulation. In other embodiments, the antifoaming agent is present inabout 2.0 mg/ml in the liquid formulation. In some embodiments, theantifoaming agent is present in about 0.05 mg/ml to about 0.3 mg/ml inthe liquid formulation. In some embodiments, the antifoaming agent ispresent in about 0.1 mg/ml to about 0.2 mg/ml in the liquid formulation.In some embodiments, the antifoaming agent is simethicone and is presentin about 0.15 mg/ml in the liquid formulation.

In some embodiments, the antifoaming agent is present in about 0.1% w/wto about 7% w/w of the solids in the liquid formulation. In otherembodiments, the antifoaming agent is present in about 0.1% w/w, about0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6%w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5%w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w,about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4%w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w,about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3%w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w,about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2%w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w,about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1%w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w,about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6%w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w,about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about6.9% w/w, or about 7% w/w of the solids in the liquid formulation.

Surfactants in the Amlodipine Liquid Formulations

Surfactants are compounds that lower the surface tension (or interfacialtension) between two liquids or between a liquid and a solid. Mostcommonly, surfactants are classified according to polar head group. Anon-ionic surfactant has no charged groups in its head. The head of anionic surfactant carries a net positive, or negative charge. If thecharge is negative, the surfactant is more specifically called anionic;if the charge is positive, it is called cationic. If a surfactantcontains a head with two oppositely charged groups, it is termedzwitterionic. Anionic surfactants contain anionic functional groups attheir head, such as sulfate, sulfonate, phosphate, and carboxylates.Prominent alkyl sulfates include ammonium lauryl sulfate, sodium laurylsulfate (sodium dodecyl sulfate, SLS, or SDS), and the relatedalkyl-ether sulfates sodium laureth sulfate (sodium lauryl ether sulfateor SLES), and sodium myreth sulfate. Others include: docusate (dioctylsodium sulfosuccinate), perfluorooctanesulfonate (PFOS),perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl etherphosphates. Cationic surfactant include pH-dependent primary, secondary,or tertiary amines such as octenidine dihydrochloride; and permanentlycharged quaternary ammonium salts such as cetrimonium bromide (CTAB),cetylpyridinium chloride (CPC), benzalkonium chloride (BAC),benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, anddioctadecyldimethylammonium bromide (DODAB). Zwitterionic (amphoteric)surfactants have both cationic and anionic centers attached to the samemolecule. The cationic part is based on primary, secondary, or tertiaryamines or quaternary ammonium cations. The anionic part can be morevariable and include sulfonates, as in the sultaines CHAPS(3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) andcocamidopropyl hydroxysultaine. Betaines such as cocamidopropyl betainehave a carboxylate with the ammonium. The most common biologicalzwitterionic surfactants have a phosphate anion with an amine orammonium, such as the phospholipids phosphatidylserine,phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.Nonionic surfactants include fatty alcohols, cetyl alcohol, stearylalcohol, and cetostearyl alcohol, and oleyl alcohol. Also used asnonionic surfactants are polyethylene glycol alkyl ethers (such asoctaethylene glycol monododecyl ether, pentaethylene glycol monododecylether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (suchas decyl glucoside, lauryl glucoside, octyl glucoside), polyethyleneglycol octylphenyl ethers (such as Triton X-100), polyethylene glycolalkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such asglyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such aspolysorbate), sorbitan alkyl esters (such as Spans), cocamide MEA,cocamide DEA, dodecyldimethylamine oxide, block copolymers ofpolyethylene glycol and polypropylene glycol (such as poloxamers), andpolyethoxylated tallow amine (POEA). The most commonly used surfactantsare fatty acid esters of sorbitan polyethoxylates, i.e. polysorbate 20and polysorbate 80. The two differ only in the length of the aliphaticchain that imparts hydrophobic character to the molecules, C-12 andC-18, respectively. Polysorbate 80 is more surface-active and has alower critical micellar concentration than polysorbate 20.

In some embodiments, the amlodipine liquid formulation described hereincomprises a surfactant. In some embodiments, the surfactant ispolysorbate 80.

In some embodiments, the surfactant is added to the amlodipine liquidformulation in separate portions during the process for preparing theamlodipine liquid formulation.

In some embodiments, the amlodipine benzoate liquid formulation isprepared by a process comprising: (i) providing an aqueous mixturecomprising an amlodipine salt that is more soluble in aqueous media thanamlodipine benzoate (e.g., amlodipine besylate); (ii) adding a saltforming agent (e.g., sodium benzoate or benzoic acid) to the aqueousmixture to form a first mixture; and (iii) subjecting the first mixtureto ultrasonic agitation thereby forming a second mixture comprisingamlodipine benzoate. In some embodiments, the process further comprisesadding the second mixture comprising amlodipine benzoate to a thirdmixture comprising one or more of a buffer, a preservative, a sweeteningagent, a suspension agent, an antifoaming agent, water, and a flavoringagent. In some embodiments, the third mixture comprises water.

In some embodiments, the surfactant is added in two separate portions.In some embodiments, a first surfactant portion is added during theformation of the pharmaceutically acceptable salt of amlodipine, e.g.,amlodipine benzoate. In some embodiments, a first surfactant portion isadded to the water prior to the formation of the aqueous mixturecomprising an amlodipine salt that is more soluble in aqueous media thanamlodipine benzoate (e.g., amlodipine besylate). In some embodiments, afirst surfactant portion is added to the aqueous mixture comprising anamlodipine salt that is more soluble in aqueous media than amlodipinebenzoate (e.g., amlodipine besylate) prior to the addition of the saltforming agent (e.g., sodium benzoate or benzoic acid). In someembodiments, a second surfactant portion is added to the second mixtureprior to the addition to the third mixture. In some embodiments, asecond surfactant portion is added to the third mixture.

In some embodiments, the surfactant is present in about 0.1 mg/ml toabout 3.0 mg/ml in the final liquid formulation. In other embodiments,the surfactant is present in about 0.1 mg/ml, about 0.15 mg/ml, about0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about1.0 mg/ml, about 1.1 mg/ml, about 1.15 mg/ml, about 1.2 mg/ml, about1.25 mg/ml, about 1.3 mg/ml, about 1.35 mg/ml, about 1.4 mg/ml, about1.45 mg/ml, about 1.5 mg/ml, about 1.55 mg/ml, about 1.6 mg/ml, about1.65 mg/ml, about 1.7 mg/ml, about 1.75 mg/ml, about 1.8 mg/ml, about1.85 mg/ml, about 1.9 mg/ml, about 1.95 mg/ml, about 2.0 mg/ml, about2.1 mg/ml, about 2.15 mg/ml, about 2.2 mg/ml, about 2.25 mg/ml, about2.3 mg/ml, about 2.35 mg/ml, about 2.4 mg/ml, about 2.45 mg/ml, about2.5 mg/ml, about 2.55 mg/ml, about 2.6 mg/ml, about 2.65 mg/ml, about2.7 mg/ml, about 2.75 mg/ml, about 2.8 mg/ml, about 2.85 mg/ml, about2.9 mg/ml, about 2.95 mg/ml, or about 3.0 mg/ml in the final liquidformulation. In some embodiments, the surfactant is polysorbate 80 andis present in about 0.5 mg/ml in the final liquid formulation. In someembodiments, the surfactant is polysorbate 80 and is present in about1.0 mg/ml in the final liquid formulation. In some embodiments, thesurfactant is polysorbate 80 and is present in about 2.0 mg/ml in thefinal liquid formulation.

In some embodiments, the surfactant is present in about 1% w/w to about15% w/w of the solids in the liquid formulation. In other embodiments,the surfactant is present in about 1%, about 1.5%, about 2%, about 2.5%,about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%,about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%,about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, or about15% of the solids in the liquid formulation.

In some embodiments, the surfactant is present in about 1% w/w to about5% w/w of the solids in the liquid formulation. In other embodiments,the surfactant is present in about 1%, about 1.1%, about 1.2%, about1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about4.9%, or about 5% of the solids in the liquid formulation.

Additional Excipients

In further embodiments, the amlodipine liquid formulation describedherein comprises additional excipients including, but not limited toflavoring agents, coloring agents and thickeners. Additional excipientssuch as bulking agents, tonicity agents and chelating agents are withinthe scope of the embodiments.

In another embodiment, the amlodipine liquid formulation comprises aflavoring agent or flavorant to enhance the taste or aroma of theformulation in liquid form. Suitable natural or synthetic flavoringagents can be selected from standard reference books, for exampleFenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).Non-limiting examples of suitable natural flavors, some of which canreadily be simulated with synthetic agents or combinations thereof,include almond, anise, apple, apricot, bergamot, blackberry,blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove,coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig,ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt,mandarin, molasses, nutmeg, mixed berry, orange, peach, pear,peppermint, pineapple, raspberry, rose, spearmint, strawberry,tangerine, tea, vanilla, wintergreen, etc. Also useful, particularlywhere the formulation is intended primarily for pediatric use, istutti-frutti or bubblegum flavor, a compounded flavoring agent based onfruit flavors. Presently preferred flavoring agents include anise,cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry),grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be usedsingly or in combinations of two or more. In certain embodiments, theamlodipine liquid formulation comprises a flavoring agent.

In further embodiments, the amlodipine liquid formulation comprises acoloring agent for identity and/or aesthetic purposes. Suitable coloringagents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C RedNo. 40, FD&C Yellow No. 6, FD&C Blue No. 2, FD&C Green No. 5, FD&COrange No. 5, caramel, ferric oxide and mixtures thereof.

Thickeners impart viscosity or weight to the resultant liquid forms fromthe amlodipine formulation described herein. Exemplary thickenersinclude dextrin, cellulose derivatives (carboxymethylcellulose and itssalts, ethylcellulose, hydroxyethyl cellulose, methylcellulose,hypromellose, and the like) starches, pectin, polyethylene glycol,polyethylene oxide, trehalose, certain silicates (magnesium aluminumsilicate, aluminum silicate, etc. such as Veegum, Bentonite, and Kaolin)and certain gums (xanthan gum, locust bean gum, etc.). In certainembodiments, the amlodipine liquid formulation comprises a thickener.

In further embodiments, the amlodipine liquid formulation does notcomprise glycerol which may cause headache, stomach upset, and diarrhea.

Additional excipients are contemplated in the amlodipine liquidformulation embodiments. These additional excipients are selected basedon function and compatibility with the amlodipine liquid formulationsdescribed herein and may be found, for example in Remington: The Scienceand Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,(Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L.,Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980);and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed(Lippincott Williams & Wilkins 1999), herein incorporated by referencein their entirety.

Particle Size

The term “D50”, as used herein, refers to a particle size in micrometerscorresponding to 50% of the volume of the sampled particles being largerthan, and 50% of the volume of the sampled particles being smaller than,the recited D50 value. Similarly, the term “D90” refers to a particlesize in micrometers corresponding to 90% of the volume of the sampledparticles being smaller than, and 10% of the volume of the sampledparticles being larger than, the recited D90 value. The term “D10”refers to a particle size in micrometers corresponding to 10% of thevolume of the sampled particles being smaller than, and 90% of thevolume of the sampled particles being larger than, the recited D10value.

In some embodiments, the suspension disclosed herein comprisesamlodipine benzoate particles having a D90 value between about 20 μm andabout 60 μm. In some embodiments, the suspension disclosed hereincomprises amlodipine benzoate particles having a D90 value between about20 μm and about 40 μm. In some embodiments, the suspension disclosedherein comprises amlodipine benzoate particles having a D90 valuebetween about 25 μm and about 35 μm. In some embodiments, the suspensiondisclosed herein comprises amlodipine benzoate particles having a D90value of about 20 μm, about 21 μm, about 22 μm, about 23 μm, about 24μm, about 25 μm, about 26 μm, about 27 μm, about 28 μm, about 29 μm,about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, about35 μm, about 36 μm, about 37 μm, about 38 μm, about 39 μm, about 40 μm,about 41 μm, about 42 μm, about 43 μm, about 44 μm, about 45 μm, about46 μm, about 47 μm, about 48 μm, about 49 μm, about 50 μm, about 51 μm,about 52 μm, about 53 μm, about 54 μm, about 55 μm, about 56 μm, about57 μm, about 58 μm, about 59 μm, or about 60 μm.

In some embodiments, the suspension disclosed herein comprisesamlodipine benzoate particles having a D50 value between about 5 μm andabout 40 μm. In some embodiments, the suspension disclosed hereincomprises amlodipine benzoate particles having a D50 value between about5 μm and about 20 μm. In some embodiments, the suspension disclosedherein comprises amlodipine benzoate particles having a D50 valuebetween about 10 μm and about 20 μm. In some embodiments, the suspensiondisclosed herein comprises amlodipine benzoate particles having a D50value of about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm,about 10 μm, about 11 μm, about 12 μm, about 13 μm, about 14 μm, about15 μm, about 16 μm, about 17 μm, about 18 μm, about 19 μm, about 20 μm,about 21 μm, about 22 μm, about 23 μm, about 24 μm, about 25 μm, about26 μm, about 27 μm, about 28 μm, about 29 μm, about 30 μm, about 31 μm,about 32 μm, about 33 μm, about 34 μm, about 35 μm, about 36 μm, about37 μm, about 38 μm, about 39 μm, or about 40 μm.

In some embodiments, the suspension disclosed herein comprisesamlodipine benzoate particles having a D10 value between about 1 μm andabout 10 μm. In some embodiments, the suspension disclosed hereincomprises amlodipine benzoate particles having a D10 value between about1 μm and about 5 μm. In some embodiments, the suspension disclosedherein comprises amlodipine benzoate particles having a D10 valuebetween about 5 μm and about 10 μm. In some embodiments, the suspensiondisclosed herein comprises amlodipine benzoate particles having a D10value of about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm,about 6 μm, about 7 μm, about 8 μm, about 9 μm, or about 10 μm.

Stability

The amlodipine liquid formulations described herein are stable invarious storage conditions including refrigerated, ambient andaccelerated conditions. Stable as used herein refers to amlodipineliquid formulations having about 95% or greater of the initialamlodipine amount and/or about 5% w/w or less total impurities orrelated substances at the end of a given storage period. In someembodiment, the impurity is amlodipine USP impurity A (A.K.A EP impurityD):

The percentage of impurities is calculated from the amount of impuritiesrelative to the amount of amlodipine. Stability is assessed by HPLC orany other known testing method. In some embodiments, the stableamlodipine liquid formulations have about 5% w/w, about 4% w/w, about 3%w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, orabout 0.5% w/w total impurities or related substances. In otherembodiments, the stable amlodipine liquid formulations have about 5% w/wtotal impurities or related substances. In yet other embodiments, thestable amlodipine liquid formulations have about 4% w/w total impuritiesor related substances. In yet other embodiments, the stable amlodipineliquid formulations have about 3% w/w total impurities or relatedsubstances. In yet other embodiments, the stable amlodipine liquidformulations have about 2% w/w total impurities or related substances.In yet other embodiments, the stable amlodipine liquid formulations haveabout 1% w/w total impurities or related substances.

At refrigerated condition, the amlodipine liquid formulations describedherein are stable for at least 1 month, at least 2 months, at least 3months, at least 6 months, at least 9 months, at least 12 months, atleast 15 months, at least 18 months, at least 24 months, at least 30months and at least 36 months. In some embodiments, refrigeratedcondition is 5±5° C. In some embodiments, refrigerated condition isabout 0° C., about 0.1° C., about 0.2° C., about 0.3° C., about 0.4° C.,about 0.5° C., about 0.6° C., about 0.7° C., about 0.8° C., about 0.9°C., about 1° C., about 1.1° C., about 1.2° C., about 1.3° C., about 1.4°C., about 1.5° C., about 1.6° C., about 1.7° C., about 1.8° C., about1.9° C., about 2° C., about 2.1° C., about 2.2° C., about 2.3° C., about2.4° C., about 2.5° C., about 2.6° C., about 2.7° C., about 2.8° C.,about 2.9° C., about 3° C., about 3.1° C., about 3.2° C., about 3.3° C.,about 3.4° C., about 3.5° C., about 3.6° C., about 3.7° C., about 3.8°C., about 3.9° C., about 4° C., about 4.1° C., about 4.2° C., about 4.3°C., about 4.4° C., about 4.5° C., about 4.6° C., about 4.7° C., about4.8° C., about 4.9° C., about 5° C., about 5.1° C., about 5.2° C., about5.3° C., about 5.4° C., about 5.5° C., about 5.6° C., about 5.7° C.,about 5.8° C., about 5.9° C., about 6° C., about 6.1° C., about 6.2° C.,about 6.3° C., about 6.4° C., about 6.5° C., about 6.6° C., about 6.7°C., about 6.8° C., about 6.9° C., about 7° C., about 7.1° C., about 7.2°C., about 7.3° C., about 7.4° C., about 7.5° C., about 7.6° C., about7.7° C., about 7.8° C., about 7.9° C., about 8° C., about 8.1° C., about8.2° C., about 8.3° C., about 8.4° C., about 8.5° C., about 8.6° C.,about 8.7° C., about 8.8° C., about 8.9° C., about 9° C., about 9.1° C.,about 9.2° C., about 9.3° C., about 9.4° C., about 9.5° C., about 9.6°C., about 9.7° C., about 9.8° C., about 9.9° C., or about 10° C. Ataccelerated conditions, the amlodipine liquid formulations describedherein are stable for at least 1 month, at least 2 months, at least 3months, at least 4 months, at least 5 months, at least 6 months, atleast 7 months, at least 8 months, at least 9 months, at least 10months, at least 11 months, at least 12 months, at least 18 months, orat least 24 months. Accelerated conditions for the amlodipine liquidformulations described herein include temperatures that are at or aboveambient levels (25±5° C.). In some instances, an accelerated conditionis at about 25° C., about 30° C., about 35° C., about 40° C., about 45°C., about 50° C., about 55° C., or about 60° C. Accelerated conditionsfor the amlodipine liquid formulations described herein also includerelative humidity (RH) that are at or above ambient levels (55±10% RH).In other instances, an accelerated condition is above 55% RH, about 65%RH, about 70% RH, about 75% RH, or about 80% RH. In further instances,an accelerated condition is about 40° C. or 60° C. at ambient humidity.In yet further instances, an accelerated condition is about 40° C. at75±5% RH humidity.

In some embodiments, the amlodipine liquid formulation is stable betweenabout 5±5° C. and about 25±5° C. for at least 12 months. In oneembodiment, the amlodipine liquid formulation is stable at about 5±5° C.for at least 12 months. In one embodiment, the amlodipine liquidformulation is stable at about 25±5° C. for at least 12 months. In oneembodiment, the amlodipine liquid formulation is stable at about 5±5° C.for at least 24 months. In one embodiment, the amlodipine liquidformulation is stable at about 25±5° C. for at least 24 months.

Kits and Articles of Manufacture

For the amlodipine liquid formulations described herein, kits andarticles of manufacture are also described. Such kits can comprise acarrier, package, or container that is compartmentalized to receive oneor more containers such as vials, tubes, and the like, each of thecontainer(s) comprising one of the separate elements to be used in amethod described herein including an amlodipine liquid formulation.Suitable containers include, for example, bottles, vials, syringes, andtest tubes. The containers can be formed from a variety of materialssuch as glass or plastic.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for an amlodipine liquid formulation described herein.Non-limiting examples of such materials include, but not limited to,buffers, diluents, filters, needles, syringes; carrier, package,container, vial and/or tube labels listing contents and/or instructionsfor use, and package inserts with instructions for use associated withan amlodipine liquid formulation. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

Method of Manufacturing

Disclosed herein is a process for preparing an amlodipine liquidformulation. In some embodiments, the amlodipine liquid formulation isin the form of a suspension. In some embodiments, the amlodipine liquidformulation comprises a pharmaceutically acceptable salt of amlodipinewhich is very slightly soluble in an aqueous media. In some embodiments,the amlodipine liquid formulation comprises a pharmaceuticallyacceptable salt of amlodipine which is practically insoluble in anaqueous media. In some embodiments, the amlodipine liquid formulationcomprises amlodipine benzoate.

Described herein are processes for preparing amlodipine benzoate andsuspensions comprising amlodipine benzoate. In some embodiment,ultrasonic agitation is used to generate the amlodipine benzoate.

Ultrasonic Agitation (Sonication)

In some embodiments, the ultrasonic agitation is carried out with anysuitable sonication device such as those described in U.S. Pat. No.5,471,001; GB 2276567; U.S. Pat. No. 6,960,256, EP 1148943, or anultrasonic cleaning tank such as described in U.S. Pat. No. 3,516,645Such devices are well known in the industry. The use of ultrasonicenergy in conjunction with a solvent for cleaning workpieces is wellestablished in the art. Cleaning apparatus of this type have beendescribed, for instance, in U.S. Pat. Nos. 2,845,077; 3,293,456;3,318,578; U.S. Pat. No. 3,651,352; and in “Ultrasonic Engineering”(book), John Wiley & Sons, New York, N.Y. (1965), pp. 130 to 143.

By “sonication” it is meant that electrical energy is converted tophysical vibrations (sound energy) which are applied to solutions,suspensions, or particles. In some embodiments, the sonication devicehas a sonication horn or probe that is inserted into the system ofinterest to emit sonic energy into the solution. In some embodiments,the sonicating device is operated at a frequency between about 1 kHz andabout 10 MHz or between about 1 kHz and about 100 kHz or between about20 kHz and about 40 kHz or any range or combination of ranges therein.In some embodiments, the frequency is modulated slightly around a targetfrequency. In some embodiments, the sonicating device is operated at afrequency of about 40 kHz with a modulation of about ±1 kHz. In someembodiments, other mixing devices such as homogenizers, blenders, orother stirring devices are used while subjecting the liquid toultrasonic agitation.

Described herein is a process for preparing amlodipine benzoate, theprocess comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine benzoate;    -   (ii) adding a salt forming agent to the aqueous mixture to form        a first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine benzoate.

In some embodiments of a method of preparing amlodipine benzoate, theprocess further comprises adjusting the pH of the aqueous mixturecomprising an amlodipine salt that is more soluble in aqueous media thanamlodipine benzoate (e.g., amlodipine besylate).

In some embodiments of a method of preparing amlodipine benzoate, theaqueous mixture further comprises a surfactant (e.g. polysorbate 80).

In some embodiments of a method of preparing amlodipine benzoate, thesurfactant (e.g., polysorbate 80) is added to the aqueous mixture ofstep (i) and mixed prior to the addition of the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate). This surfactant addition prior to the addition of theamlodipine salt that is more soluble in aqueous media that amlodipinebenzoate (e.g., amlodipine besylate) minimizes the potential foramlodipine to adhere to metal containers such as those made of stainlesssteel.

In some embodiments of a method of preparing amlodipine benzoate, theaqueous mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate) andthe surfactant (e.g., polysorbate 80) is mixed prior to the addition ofthe salt forming agent (e.g., sodium benzoate or benzoic acid) in step(ii). This mixing ensures an even dispersion of the amlodipine salt andthe surfactant (e.g., polysorbate 80). In some embodiments of a methodof preparing amlodipine benzoate, the mixing prior to the addition ofthe salt forming agent (e.g., sodium benzoate or benzoic acid) in step(ii) is performed for between about 1 minute and about 10 minutes. Insome embodiments of a method of preparing amlodipine benzoate, themixing prior to the addition of the salt forming agent (e.g., sodiumbenzoate or benzoic acid) in step (ii) is performed for about 1 minute,about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes,about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, orabout 10 minutes.

In some embodiments of a method of preparing amlodipine benzoate, thefirst mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate), thesurfactant (e.g., polysorbate 80), and the salt forming agent (e.g.,sodium benzoate or benzoic acid) is mixed before being subjected toultrasonic agitation.

In some embodiments of a method of preparing amlodipine benzoate, thefirst mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate), thesurfactant (e.g., polysorbate 80), and the salt forming agent (e.g.,sodium benzoate or benzoic acid) is mixed while being subjected toultrasonic agitation.

In some embodiments of a method of preparing amlodipine benzoate, thefirst mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate), thesurfactant (e.g., polysorbate 80), and the salt forming agent (e.g.,sodium benzoate or benzoic acid) is mixed after being subjected toultrasonic agitation.

In some embodiments of a method of preparing amlodipine benzoate, themixing after being subjected to ultrasonic agitation is performed forbetween about 1 minute and about 30 minutes. In some embodiments of amethod of preparing amlodipine benzoate, the mixing after beingsubjected to ultrasonic agitation is performed for between about 10minutes and about 30 minutes. In some embodiments of a method ofpreparing amlodipine benzoate, the mixing after being subjected toultrasonic agitation is performed for about 10 minutes, about 11 minute,about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes,about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes,about 20 minutes, about 21 minute, about 22 minutes, about 23 minutes,about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes,about 28 minutes, about 29 minutes, or about 30 minutes.

In some embodiments of a method of preparing amlodipine benzoate, thefrequency of the ultrasonic agitation is between about 20 kHz and about100 kHz. In some embodiments of a method of preparing amlodipinebenzoate, the frequency of the ultrasonic agitation is about 20 kHz. Insome embodiments of a method of preparing amlodipine benzoate, thefrequency of the ultrasonic agitation is about 40 kHz. In someembodiments of a method of preparing amlodipine benzoate, the frequencyof the ultrasonic agitation is modulated about ±1 kHz around the desiredfrequency.

In some embodiments of a method of preparing amlodipine benzoate, theduration of the ultrasonic agitation is between about 1 minute and 1hour. In some embodiments of a method of preparing amlodipine benzoate,the duration of the ultrasonic agitation is about 1 minute, about 5minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45minutes, about 50 minutes, about 55 minutes, or about 1 hour. In someembodiments of a method of preparing amlodipine benzoate, the durationof the ultrasonic agitation is between about 5 minutes and 30 minutes.In some embodiments of a method of preparing amlodipine benzoate, theduration of the ultrasonic agitation is between about 5 minutes and 20minutes. In some embodiments of a method of preparing amlodipinebenzoate, the duration of the ultrasonic agitation is about 5 minutes.In some embodiments of a method of preparing amlodipine benzoate, theduration of the ultrasonic agitation is about 10 minutes.

In some embodiments of a method of preparing amlodipine benzoate, thetemperature of the first mixture or second mixture is not controlled.

In some embodiments of a method of preparing amlodipine benzoate, theprocess does not involve the use of any solvent other than water.

Described herein is a process for preparing amlodipine benzoate, theprocess comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine benzoate;    -   (ii) adding sodium benzoate to the aqueous mixture to form a        first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine benzoate.

In some embodiments of a method of preparing amlodipine benzoate, theaqueous mixture further comprises a surfactant (e.g., polysorbate 80).

In some embodiments of a method of preparing amlodipine benzoate, thesurfactant (e.g., polysorbate 80) is added to the aqueous mixture ofstep (i) and mixed prior to the addition of the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate). This surfactant addition prior to the addition of theamlodipine salt that is more soluble in aqueous media that amlodipinebenzoate (e.g., amlodipine besylate) minimizes the potential foramlodipine to adhere to metal containers such as those made of stainlesssteel.

In some embodiments of a method of preparing amlodipine benzoate, theaqueous mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate) andthe surfactant (e.g., polysorbate 80) is mixed prior to the addition ofsodium benzoate in step (ii). This mixing ensures an even dispersion ofthe amlodipine salt and the surfactant (e.g., polysorbate 80). In someembodiments of a method of preparing amlodipine benzoate, the mixingprior to the addition of sodium benzoate in step (ii) is performed forbetween about 1 minute and about 10 minutes. In some embodiments of amethod of preparing amlodipine benzoate, the mixing prior to theaddition of sodium benzoate in step (ii) is performed for about 1minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9minutes, or about 10 minutes.

In some embodiments of a method of preparing amlodipine benzoate, thefirst mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate), thesurfactant (e.g., polysorbate 80), and sodium benzoate is mixed beforebeing subjected to ultrasonic agitation.

In some embodiments of a method of preparing amlodipine benzoate, thefirst mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate), thesurfactant (e.g., polysorbate 80), and sodium benzoate is mixed whilebeing subjected to ultrasonic agitation.

In some embodiments of a method of preparing amlodipine benzoate, thefirst mixture comprising the amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate), thesurfactant (e.g., polysorbate 80), and sodium benzoate is mixed afterbeing subjected to ultrasonic agitation.

In some embodiments of a method of preparing amlodipine benzoate, themixing after being subjected to ultrasonic agitation is performed forbetween about 1 minute and about 30 minutes. In some embodiments of amethod of preparing amlodipine benzoate, the mixing after beingsubjected to ultrasonic agitation is performed for between about 10minutes and about 30 minutes. In some embodiments of a method ofpreparing amlodipine benzoate, the mixing after being subjected toultrasonic agitation is performed for about 10 minutes, about 11 minute,about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes,about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes,about 20 minutes, about 21 minute, about 22 minutes, about 23 minutes,about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes,about 28 minutes, about 29 minutes, or about 30 minutes.

In some embodiments of a method of preparing amlodipine benzoate, thefrequency of the ultrasonic agitation is between about 20 kHz and about100 kHz. In some embodiments of a method of preparing amlodipinebenzoate, the frequency of the ultrasonic agitation is about 20 kHz. Insome embodiments of a method of preparing amlodipine benzoate, thefrequency of the ultrasonic agitation is about 40 kHz. In someembodiments of a method of preparing amlodipine benzoate, the frequencyof the ultrasonic agitation is modulated about ±1 kHz around the desiredfrequency.

In some embodiments of a method of preparing amlodipine benzoate, theduration of the ultrasonic agitation is between about 1 minute and 1hour. In some embodiments of a method of preparing amlodipine benzoate,the duration of the ultrasonic agitation is about 1 minute, about 5minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45minutes, about 50 minutes, about 55 minutes, or about 1 hour. In someembodiments of a method of preparing amlodipine benzoate, the durationof the ultrasonic agitation is between about 5 minutes and 30 minutes.In some embodiments of a method of preparing amlodipine benzoate, theduration of the ultrasonic agitation is between about 5 minutes and 20minutes. In some embodiments of a method of preparing amlodipinebenzoate, the duration of the ultrasonic agitation is about 5 minutes.In some embodiments of a method of preparing amlodipine benzoate, theduration of the ultrasonic agitation is about 10 minutes.

In some embodiments of a method of preparing amlodipine benzoate, thetemperature of the first mixture or second mixture is not controlled.

In some embodiments of a method of preparing amlodipine benzoate, theprocess does not involve the use of any solvent other than water.

Described herein is a process for preparing amlodipine naphthalenesulfonate, the process comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine        naphthalene sulfonate;    -   (ii) adding a salt forming agent to the aqueous mixture to form        a first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine        naphthalene sulfonate.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the process further comprises adjusting the pH of the aqueousmixture comprising an amlodipine salt that is more soluble in aqueousmedia than amlodipine naphthalene sulfonate (e.g., amlodipine besylate).

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the aqueous mixture further comprises a surfactant (e.g.polysorbate 80).

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the surfactant (e.g., polysorbate 80) is added to the aqueousmixture of step (i) and mixed prior to the addition of the amlodipinesalt that is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate). This surfactant addition prior tothe addition of the amlodipine salt that is more soluble in aqueousmedia that amlodipine naphthalene sulfonate (e.g., amlodipine besylate)minimizes the potential for amlodipine to adhere to metal containerssuch as those made of stainless steel.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the aqueous mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine naphthalene sulfonate(e.g., amlodipine besylate) and the surfactant (e.g., polysorbate 80) ismixed prior to the addition of the salt forming agent (e.g., sodiumnaphthalene-2-sulfonate) in step (ii). This mixing ensures an evendispersion of the amlodipine salt and the surfactant (e.g., polysorbate80). In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the mixing prior to the addition of the salt forming agent(e.g., sodium naphthalene-2-sulfonate) in step (ii) is performed forbetween about 1 minute and about 10 minutes. In some embodiments of amethod of preparing amlodipine naphthalene sulfonate, the mixing priorto the addition of the salt forming agent (e.g., sodiumnaphthalene-2-sulfonate) in step (ii) is performed for about 1 minute,about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes,about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, orabout 10 minutes.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the first mixture comprising the amlodipine salt that is moresoluble in aqueous media than amlodipine naphthalene sulfonate (e.g.,amlodipine besylate), the surfactant (e.g., polysorbate 80), and thesalt forming agent (e.g., sodium naphthalene-2-sulfonate) is mixedbefore being subjected to ultrasonic agitation.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the first mixture comprising the amlodipine salt that is moresoluble in aqueous media than amlodipine naphthalene sulfonate (e.g.,amlodipine besylate), the surfactant (e.g., polysorbate 80), and thesalt forming agent (e.g., sodium naphthalene-2-sulfonate) is mixed whilebeing subjected to ultrasonic agitation.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the first mixture comprising the amlodipine salt that is moresoluble in aqueous media than amlodipine naphthalene sulfonate (e.g.,amlodipine besylate), the surfactant (e.g., polysorbate 80), and thesalt forming agent (e.g., sodium naphthalene-2-sulfonate) is mixed afterbeing subjected to ultrasonic agitation.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the mixing after being subjected to ultrasonic agitation isperformed for between about 1 minute and about 30 minutes. In someembodiments of a method of preparing amlodipine naphthalene sulfonate,the mixing after being subjected to ultrasonic agitation is performedfor between about 10 minutes and about 30 minutes. In some embodimentsof a method of preparing amlodipine naphthalene sulfonate, the mixingafter being subjected to ultrasonic agitation is performed for about 10minutes, about 11 minute, about 12 minutes, about 13 minutes, about 14minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18minutes, about 19 minutes, about 20 minutes, about 21 minute, about 22minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about30 minutes.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the frequency of the ultrasonic agitation is between about 20kHz and about 100 kHz. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the frequency of the ultrasonicagitation is about 20 kHz. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the frequency of the ultrasonicagitation is about 40 kHz. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the frequency of the ultrasonicagitation is modulated about ±1 kHz around the desired frequency.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the duration of the ultrasonic agitation is between about 1minute and 1 hour. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the duration of the ultrasonicagitation is about 1 minute, about 5 minutes, about 10 minutes, about 15minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55minutes, or about 1 hour. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the duration of the ultrasonicagitation is between about 5 minutes and 30 minutes. In some embodimentsof a method of preparing amlodipine naphthalene sulfonate, the durationof the ultrasonic agitation is between about 5 minutes and 20 minutes.In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the duration of the ultrasonic agitation is about 5 minutes.In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the duration of the ultrasonic agitation is about 10 minutes.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the temperature of the first mixture or second mixture is notcontrolled.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the process does not involve the use of any solvent otherthan water.

Described herein is a process for preparing amlodipine naphthalenesulfonate, the process comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine        naphthalene sulfonate;    -   (ii) adding sodium naphthalene-2-sulfonate to the aqueous        mixture to form a first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine        naphthalene sulfonate.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the aqueous mixture further comprises a surfactant (e.g.,polysorbate 80).

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the surfactant (e.g., polysorbate 80) is added to the aqueousmixture of step (i) and mixed prior to the addition of the amlodipinesalt that is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate). This surfactant addition prior tothe addition of the amlodipine salt that is more soluble in aqueousmedia that amlodipine naphthalene sulfonate (e.g., amlodipine besylate)minimizes the potential for amlodipine to adhere to metal containerssuch as those made of stainless steel.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the aqueous mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine naphthalene sulfonate(e.g., amlodipine besylate) and the surfactant (e.g., polysorbate 80) ismixed prior to the addition of sodium naphthalene-2-sulfonate in step(ii). This mixing ensures an even dispersion of the amlodipine salt andthe surfactant (e.g., polysorbate 80). In some embodiments of a methodof preparing amlodipine naphthalene sulfonate, the mixing prior to theaddition of sodium naphthalene-2-sulfonate in step (ii) is performed forbetween about 1 minute and about 10 minutes. In some embodiments of amethod of preparing amlodipine naphthalene sulfonate, the mixing priorto the addition of sodium naphthalene-2-sulfonate in step (ii) isperformed for about 1 minute, about 2 minutes, about 3 minutes, about 4minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8minutes, about 9 minutes, or about 10 minutes.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the first mixture comprising the amlodipine salt that is moresoluble in aqueous media than amlodipine naphthalene sulfonate (e.g.,amlodipine besylate), the surfactant (e.g., polysorbate 80), and sodiumnaphthalene-2-sulfonate is mixed before being subjected to ultrasonicagitation.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the first mixture comprising the amlodipine salt that is moresoluble in aqueous media than amlodipine naphthalene sulfonate (e.g.,amlodipine besylate), the surfactant (e.g., polysorbate 80), and sodiumnaphthalene-2-sulfonate is mixed while being subjected to ultrasonicagitation.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the first mixture comprising the amlodipine salt that is moresoluble in aqueous media than amlodipine naphthalene sulfonate (e.g.,amlodipine besylate), the surfactant (e.g., polysorbate 80), and sodiumnaphthalene-2-sulfonate is mixed after being subjected to ultrasonicagitation.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the mixing after being subjected to ultrasonic agitation isperformed for between about 1 minute and about 30 minutes. In someembodiments of a method of preparing amlodipine naphthalene sulfonate,the mixing after being subjected to ultrasonic agitation is performedfor between about 10 minutes and about 30 minutes. In some embodimentsof a method of preparing amlodipine naphthalene sulfonate, the mixingafter being subjected to ultrasonic agitation is performed for about 10minutes, about 11 minute, about 12 minutes, about 13 minutes, about 14minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18minutes, about 19 minutes, about 20 minutes, about 21 minute, about 22minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about30 minutes.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the frequency of the ultrasonic agitation is between about 20kHz and about 100 kHz. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the frequency of the ultrasonicagitation is about 20 kHz. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the frequency of the ultrasonicagitation is about 40 kHz. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the frequency of the ultrasonicagitation is modulated about ±1 kHz around the desired frequency.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the duration of the ultrasonic agitation is between about 1minute and 1 hour. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the duration of the ultrasonicagitation is about 1 minute, about 5 minutes, about 10 minutes, about 15minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55minutes, or about 1 hour. In some embodiments of a method of preparingamlodipine naphthalene sulfonate, the duration of the ultrasonicagitation is between about 5 minutes and 30 minutes. In some embodimentsof a method of preparing amlodipine naphthalene sulfonate, the durationof the ultrasonic agitation is between about 5 minutes and 20 minutes.In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the duration of the ultrasonic agitation is about 5 minutes.In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the duration of the ultrasonic agitation is about 10 minutes.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the temperature of the first mixture or second mixture is notcontrolled.

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the process does not involve the use of any solvent otherthan water.

Described herein is a process for preparing an amlodipine benzoatesuspension, the process comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine benzoate;    -   (ii) adding a salt forming agent to the aqueous mixture to form        a first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine benzoate.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adjusting the pH of theaqueous mixture comprising an amlodipine salt that is more soluble inaqueous media than amlodipine benzoate (e.g., amlodipine besylate).

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the aqueous mixture further comprises a surfactant (e.g.polysorbate 80).

In some embodiments of a method of preparing amlodipine benzoate, thesurfactant (e.g., polysorbate 80) is added to the aqueous mixture ofstep (i) and mixed prior to the addition of the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate). This surfactant addition prior to the addition of theamlodipine salt that is more soluble in aqueous media that amlodipinebenzoate (e.g., amlodipine besylate) minimizes the potential foramlodipine to adhere to metal containers such as those made of stainlesssteel.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the aqueous mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate) and the surfactant (e.g., polysorbate 80) is mixed prior tothe addition of the salt forming agent (e.g., sodium benzoate or benzoicacid) in step (ii). This mixing ensures an even dispersion of theamlodipine salt and the surfactant (e.g., polysorbate 80). In someembodiments of a method of preparing an amlodipine benzoate suspension,the mixing prior to the addition of the salt forming agent (e.g., sodiumbenzoate or benzoic acid) in step (ii) is performed for between about 1minute and about 10 minutes. In some embodiments of a method ofpreparing an amlodipine benzoate suspension, the mixing prior to theaddition of the salt forming agent (e.g., sodium benzoate or benzoicacid) in step (ii) is performed for about 1 minute, about 2 minutes,about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes,about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate), the surfactant (e.g., polysorbate 80), and the salt formingagent (e.g., sodium benzoate or benzoic acid) is mixed before beingsubjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate), the surfactant (e.g., polysorbate 80), and the salt formingagent (e.g., sodium benzoate or benzoic acid) is mixed while beingsubjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate), the surfactant (e.g., polysorbate 80), and the salt formingagent (e.g., sodium benzoate or benzoic acid) is mixed after beingsubjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the mixing after being subjected to ultrasonic agitation isperformed for between about 1 minute and about 30 minutes. In someembodiments of a method of preparing an amlodipine benzoate suspension,the mixing after being subjected to ultrasonic agitation is performedfor between about 10 minutes and about 30 minutes. In some embodimentsof a method of preparing an amlodipine benzoate suspension, the mixingafter being subjected to ultrasonic agitation is performed for about 10minutes, about 11 minute, about 12 minutes, about 13 minutes, about 14minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18minutes, about 19 minutes, about 20 minutes, about 21 minute, about 22minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about30 minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the frequency of the ultrasonic agitation is between about20 kHz and about 100 kHz. In some embodiments of a method of preparingan amlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 20 kHz. In some embodiments of a method of preparingan amlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 40 kHz. In some embodiments of a method of preparingamlodipine benzoate, the frequency of the ultrasonic agitation ismodulated about ±1 kHz around the desired frequency.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is between about 1minute and 1 hour. In some embodiments of a method of preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes,about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes,about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes,or about 1 hour. In some embodiments of a method of preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis between about 5 minutes and 30 minutes. In some embodiments of amethod of preparing an amlodipine benzoate suspension, the duration ofthe ultrasonic agitation is between about 5 minutes and 20 minutes. Insome embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is about 5 minutes.In some embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is about 10minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the temperature of the first mixture or second mixture isnot controlled.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process does not involve the use of any solvent otherthan water.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding the second mixturecomprising amlodipine benzoate to a third mixture comprising one or moreof a buffer, a preservative, a sweetening agent, a suspension agent, anantifoaming agent, water, and a flavoring agent. In some embodiments,the third mixture comprises water.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding a second surfactant(e.g., polysorbate 80).

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the second surfactant (e.g., polysorbate 80) is added to thesecond mixture and/or the third mixture.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the second surfactant is added to the second mixturecomprising amlodipine benzoate.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, a second surfactant is added to the third mixture comprisingone or more of a buffer, a preservative, a sweetening agent, asuspension agent, an antifoaming agent, and a flavoring agent.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding water quantum satisthereby forming the amlodipine benzoate suspension.

Also disclosed herein is a process for preparing an amlodipine benzoatesuspension, the process comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine benzoate;    -   (ii) adding sodium benzoate to the aqueous mixture to form a        first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine benzoate.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the aqueous mixture further comprises a surfactant (e.g.,polysorbate 80).

In some embodiments of a method of preparing amlodipine benzoate, thesurfactant (e.g., polysorbate 80) is added to the aqueous mixture ofstep (i) and mixed prior to the addition of the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate). This surfactant addition prior to the addition of theamlodipine salt that is more soluble in aqueous media that amlodipinebenzoate (e.g., amlodipine besylate) minimizes the potential foramlodipine to adhere to metal containers such as those made of stainlesssteel.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the aqueous mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate) and the surfactant (e.g., polysorbate 80) is mixed prior tothe addition of sodium benzoate in step (ii). This mixing ensures aneven dispersion of the amlodipine salt and the surfactant (e.g.,polysorbate 80). In some embodiments of a method of preparing anamlodipine benzoate suspension, the mixing prior to the addition ofsodium benzoate in step (ii) is performed for between about 1 minute andabout 10 minutes. In some embodiments of a method of preparing anamlodipine benzoate suspension, the mixing prior to the addition ofsodium benzoate in step (ii) is performed for about 1 minute, about 2minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate), the surfactant (e.g., polysorbate 80), and sodium benzoate ismixed before being subjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate), the surfactant (e.g., polysorbate 80), and sodium benzoate ismixed while being subjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising the amlodipine salt that ismore soluble in aqueous media than amlodipine benzoate (e.g., amlodipinebesylate), the surfactant (e.g., polysorbate 80), and sodium benzoate ismixed after being subjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the mixing after being subjected to ultrasonic agitation isperformed for between about 1 minute and about 30 minutes. In someembodiments of a method of preparing an amlodipine benzoate suspension,the mixing after being subjected to ultrasonic agitation is performedfor between about 10 minutes and about 30 minutes. In some embodimentsof a method of preparing an amlodipine benzoate suspension, the mixingafter being subjected to ultrasonic agitation is performed for about 10minutes, about 11 minute, about 12 minutes, about 13 minutes, about 14minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18minutes, about 19 minutes, about 20 minutes, about 21 minute, about 22minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about30 minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the frequency of the ultrasonic agitation is between about20 kHz and about 100 kHz. In some embodiments of a method of preparingan amlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 20 kHz. In some embodiments of a method of preparingan amlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 40 kHz. In some embodiments of a method of preparingamlodipine benzoate, the frequency of the ultrasonic agitation ismodulated about ±1 kHz around the desired frequency.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is between about 1minute and 1 hour. In some embodiments of a method of preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes,about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes,about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes,or about 1 hour. In some embodiments of a method of preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis between about 5 minutes and 30 minutes. In some embodiments of amethod of preparing an amlodipine benzoate suspension, the duration ofthe ultrasonic agitation is between about 5 minutes and 20 minutes. Insome embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is about 5 minutes.In some embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is about 10minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the temperature of the first mixture or the second mixtureis not controlled.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process does not involve the use of any solvent otherthan water.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding the second mixturecomprising amlodipine benzoate to a third mixture comprising one or moreof a buffer, a preservative, a sweetening agent, a suspension agent, anantifoaming agent, water, and a flavoring agent. In some embodiments,the third mixture comprises water.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding a second surfactant(e.g., polysorbate 80).

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the second surfactant (e.g., polysorbate 80) is added to thesecond mixture and/or the third mixture.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the second surfactant is added to the second mixturecomprising amlodipine benzoate.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, a second surfactant is added to the third mixture comprisingone or more of a buffer, a preservative, a sweetening agent, asuspension agent, an antifoaming agent, water, and a flavoring agent.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding water quantum satisthereby forming the amlodipine benzoate suspension.

Described herein is a process for preparing an amlodipine naphthalenesulfonate suspension, the process comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine        naphthalene sulfonate;    -   (ii) adding a salt forming agent to the aqueous mixture to form        a first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine        naphthalene sulfonate.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process further comprises adjusting the pH ofthe aqueous mixture comprising an amlodipine salt that is more solublein aqueous media than amlodipine naphthalene sulfonate (e.g., amlodipinebesylate).

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the aqueous mixture further comprises a surfactant(e.g. polysorbate 80).

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the surfactant (e.g., polysorbate 80) is added to the aqueousmixture of step (i) and mixed prior to the addition of the amlodipinesalt that is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate). This surfactant addition prior tothe addition of the amlodipine salt that is more soluble in aqueousmedia that amlodipine naphthalene sulfonate (e.g., amlodipine besylate)minimizes the potential for amlodipine to adhere to metal containerssuch as those made of stainless steel.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the aqueous mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate) and the surfactant (e.g.,polysorbate 80) is mixed prior to the addition of the salt forming agent(e.g., sodium naphthalene-2-sulfonate) in step (ii). This mixing ensuresan even dispersion of the amlodipine salt and the surfactant (e.g.,polysorbate 80). In some embodiments of a method of preparing anamlodipine naphthalene sulfonate suspension, the mixing prior to theaddition of the salt forming agent (e.g., sodiumnaphthalene-2-sulfonate) in step (ii) is performed for between about 1minute and about 10 minutes. In some embodiments of a method ofpreparing an amlodipine naphthalene sulfonate suspension, the mixingprior to the addition of the salt forming agent (e.g., sodiumnaphthalene-2-sulfonate) in step (ii) is performed for about 1 minute,about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes,about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, orabout 10 minutes.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the first mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate), the surfactant (e.g., polysorbate80), and the salt forming agent (e.g., sodium naphthalene-2-sulfonate)is mixed before being subjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the first mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate), the surfactant (e.g., polysorbate80), and the salt forming agent (e.g., sodium naphthalene-2-sulfonate)is mixed while being subjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the first mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate), the surfactant (e.g., polysorbate80), and the salt forming agent (e.g., sodium naphthalene-2-sulfonate)is mixed after being subjected to ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the mixing after being subjected to ultrasonicagitation is performed for between about 1 minute and about 30 minutes.In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the mixing after being subjected to ultrasonicagitation is performed for between about 10 minutes and about 30minutes. In some embodiments of a method of preparing an amlodipinenaphthalene sulfonate suspension, the mixing after being subjected toultrasonic agitation is performed for about 10 minutes, about 11 minute,about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes,about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes,about 20 minutes, about 21 minute, about 22 minutes, about 23 minutes,about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes,about 28 minutes, about 29 minutes, or about 30 minutes.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the frequency of the ultrasonic agitation isbetween about 20 kHz and about 100 kHz. In some embodiments of a methodof preparing an amlodipine naphthalene sulfonate suspension, thefrequency of the ultrasonic agitation is about 20 kHz. In someembodiments of a method of preparing an amlodipine naphthalene sulfonatesuspension, the frequency of the ultrasonic agitation is about 40 kHz.In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the frequency of the ultrasonic agitation is modulated about±1 kHz around the desired frequency.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the duration of the ultrasonic agitation isbetween about 1 minute and 1 hour. In some embodiments of a method ofpreparing an amlodipine naphthalene sulfonate suspension, the durationof the ultrasonic agitation is about 1 minute, about 5 minutes, about 10minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50minutes, about 55 minutes, or about 1 hour. In some embodiments of amethod of preparing an amlodipine naphthalene sulfonate suspension, theduration of the ultrasonic agitation is between about 5 minutes and 30minutes. In some embodiments of a method of preparing an amlodipinenaphthalene sulfonate suspension, the duration of the ultrasonicagitation is between about 5 minutes and 20 minutes. In some embodimentsof a method of preparing an amlodipine naphthalene sulfonate suspension,the duration of the ultrasonic agitation is about 5 minutes. In someembodiments of a method of preparing an amlodipine naphthalene sulfonatesuspension, the duration of the ultrasonic agitation is about 10minutes.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the temperature of the first mixture or secondmixture is not controlled.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process does not involve the use of anysolvent other than water.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process further comprises adding the secondmixture comprising amlodipine naphthalene sulfonate to a third mixturecomprising one or more of a buffer, a preservative, a sweetening agent,a suspension agent, an antifoaming agent, water, and a flavoring agent.In some embodiments, the third mixture comprises water.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process further comprises adding a secondsurfactant (e.g., polysorbate 80).

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the second surfactant (e.g., polysorbate 80) isadded to the second mixture and/or the third mixture.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the second surfactant is added to the secondmixture comprising amlodipine naphthalene sulfonate.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, a second surfactant is added to the third mixturecomprising one or more of a buffer, a preservative, a sweetening agent,a suspension agent, an antifoaming agent, water, and a flavoring agent.In some embodiments, the third mixture comprises water.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process further comprises adding water quantumsatis thereby forming the amlodipine naphthalene sulfonate suspension.

Also disclosed herein is a process for preparing an amlodipinenaphthalene sulfonate suspension, the process comprising:

-   -   (i) providing an aqueous mixture comprising an amlodipine salt        that is more soluble in aqueous media than amlodipine        naphthalene sulfonate;    -   (ii) adding sodium naphthalene-2-sulfonate to the aqueous        mixture to form a first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine        naphthalene sulfonate.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the aqueous mixture further comprises a surfactant(e.g., polysorbate 80).

In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the surfactant (e.g., polysorbate 80) is added to the aqueousmixture of step (i) and mixed prior to the addition of the amlodipinesalt that is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate). This surfactant addition prior tothe addition of the amlodipine salt that is more soluble in aqueousmedia that amlodipine naphthalene sulfonate (e.g., amlodipine besylate)minimizes the potential for amlodipine to adhere to metal containerssuch as those made of stainless steel.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the aqueous mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate) and the surfactant (e.g.,polysorbate 80) is mixed prior to the addition of sodiumnaphthalene-2-sulfonate in step (ii). This mixing ensures an evendispersion of the amlodipine salt and the surfactant (e.g., polysorbate80). In some embodiments of a method of preparing an amlodipinenaphthalene sulfonate suspension, the mixing prior to the addition ofsodium naphthalene-2-sulfonate in step (ii) is performed for betweenabout 1 minute and about 10 minutes. In some embodiments of a method ofpreparing an amlodipine naphthalene sulfonate suspension, the mixingprior to the addition of sodium naphthalene-2-sulfonate in step (ii) isperformed for about 1 minute, about 2 minutes, about 3 minutes, about 4minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8minutes, about 9 minutes, or about 10 minutes.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the first mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate), the surfactant (e.g., polysorbate80), and sodium naphthalene-2-sulfonate is mixed before being subjectedto ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the first mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate), the surfactant (e.g., polysorbate80), and sodium naphthalene-2-sulfonate is mixed while being subjectedto ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the first mixture comprising the amlodipine saltthat is more soluble in aqueous media than amlodipine naphthalenesulfonate (e.g., amlodipine besylate), the surfactant (e.g., polysorbate80), and sodium naphthalene-2-sulfonate is mixed after being subjectedto ultrasonic agitation.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the mixing after being subjected to ultrasonicagitation is performed for between about 1 minute and about 30 minutes.In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the mixing after being subjected to ultrasonicagitation is performed for between about 10 minutes and about 30minutes. In some embodiments of a method of preparing an amlodipinenaphthalene sulfonate suspension, the mixing after being subjected toultrasonic agitation is performed for about 10 minutes, about 11 minute,about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes,about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes,about 20 minutes, about 21 minute, about 22 minutes, about 23 minutes,about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes,about 28 minutes, about 29 minutes, or about 30 minutes.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the frequency of the ultrasonic agitation isbetween about 20 kHz and about 100 kHz. In some embodiments of a methodof preparing an amlodipine naphthalene sulfonate suspension, thefrequency of the ultrasonic agitation is about 20 kHz. In someembodiments of a method of preparing an amlodipine naphthalene sulfonatesuspension, the frequency of the ultrasonic agitation is about 40 kHz.In some embodiments of a method of preparing amlodipine naphthalenesulfonate, the frequency of the ultrasonic agitation is modulated about±1 kHz around the desired frequency.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the duration of the ultrasonic agitation isbetween about 1 minute and 1 hour. In some embodiments of a method ofpreparing an amlodipine naphthalene sulfonate suspension, the durationof the ultrasonic agitation is about 1 minute, about 5 minutes, about 10minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50minutes, about 55 minutes, or about 1 hour. In some embodiments of amethod of preparing an amlodipine naphthalene sulfonate suspension, theduration of the ultrasonic agitation is between about 5 minutes and 30minutes. In some embodiments of a method of preparing an amlodipinenaphthalene sulfonate suspension, the duration of the ultrasonicagitation is between about 5 minutes and 20 minutes. In some embodimentsof a method of preparing an amlodipine naphthalene sulfonate suspension,the duration of the ultrasonic agitation is about 5 minutes. In someembodiments of a method of preparing an amlodipine naphthalene sulfonatesuspension, the duration of the ultrasonic agitation is about 10minutes.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the temperature of the first mixture or the secondmixture is not controlled.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process does not involve the use of anysolvent other than water.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process further comprises adding the secondmixture comprising amlodipine naphthalene sulfonate to a third mixturecomprising one or more of a buffer, a preservative, a sweetening agent,a suspension agent, an antifoaming agent, water, and a flavoring agent.In some embodiments, the third mixture comprises water.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process further comprises adding a secondsurfactant (e.g., polysorbate 80).

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the second surfactant (e.g., polysorbate 80) isadded to the second mixture and/or the third mixture.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the second surfactant is added to the secondmixture comprising amlodipine naphthalene sulfonate.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, a second surfactant is added to the third mixturecomprising one or more of a buffer, a preservative, a sweetening agent,a suspension agent, an antifoaming agent, and a flavoring agent.

In some embodiments of a method of preparing an amlodipine naphthalenesulfonate suspension, the process further comprises adding water quantumsatis thereby forming the amlodipine naphthalene sulfonate suspension.

Also disclosed herein is a process for preparing an amlodipine benzoatesuspension, the process comprising:

-   -   (i) providing an amlodipine besylate aqueous mixture;    -   (ii) adding sodium benzoate to the aqueous mixture to form a        first mixture;    -   (iii) subjecting the first mixture to ultrasonic agitation        thereby forming a second mixture comprising amlodipine benzoate;    -   (iv) combining the second mixture with a third mixture        comprising sucralose, silicon dioxide, hydroxypropyl        methylcellulose, simethicone, a citrate buffer, and optionally a        flavoring agent to obtain the amlodipine benzoate suspension;    -   the amlodipine benzoate suspension comprising:        -   a) amlodipine benzoate in an amount corresponding to 1.0            mg/ml amlodipine freebase;        -   b) about 3 mM of a citrate buffer;        -   c) about 0.2 mg/ml to about 5.0 mg/ml of sodium benzoate;        -   d) about 0.7 mg/mL sucralose;        -   e) about 0.5 mg/ml of silicon dioxide;        -   f) about 7.5 mg/ml of hydroxypropyl methylcellulose;        -   g) about 0.5 mg/ml simethicone;        -   h) about 1.0 mg/ml of polysorbate 80; and        -   i) water.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the aqueous mixture further comprises a first portion ofpolysorbate 80.

In some embodiments of a method of preparing amlodipine benzoate, thepolysorbate 80 is added to the aqueous mixture of step (i) and mixedprior to the addition of amlodipine besylate. This surfactant additionprior to the addition of amlodipine besylate minimizes the potential foramlodipine to adhere to metal containers such as those made of stainlesssteel.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the aqueous mixture comprising the amlodipine besylate andpolysorbate 80 is mixed prior to the addition of sodium benzoate in step(ii). This mixing ensures an even dispersion of the amlodipine besylateand polysorbate 80. In some embodiments of a method of preparing anamlodipine benzoate suspension, the mixing prior to the addition ofsodium benzoate in step (ii) is performed for between about 1 minute andabout 10 minutes. In some embodiments of a method of preparing anamlodipine benzoate suspension, the mixing prior to the addition ofsodium benzoate in step (ii) is performed for about 1 minute, about 2minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising amlodipine besylate,polysorbate 80, and sodium benzoate is mixed before being subjected toultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising amlodipine besylate,polysorbate 80, and sodium benzoate is mixed while being subjected toultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the first mixture comprising amlodipine besylate,polysorbate 80, and sodium benzoate is mixed after being subjected toultrasonic agitation.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the mixing after being subjected to ultrasonic agitation isperformed for between about 1 minute and about 30 minutes. In someembodiments of a method of preparing an amlodipine benzoate suspension,the mixing after being subjected to ultrasonic agitation is performedfor between about 10 minutes and about 30 minutes. In some embodimentsof a method of preparing an amlodipine benzoate suspension, the mixingafter being subjected to ultrasonic agitation is performed for about 10minutes, about 11 minute, about 12 minutes, about 13 minutes, about 14minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18minutes, about 19 minutes, about 20 minutes, about 21 minute, about 22minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about30 minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the frequency of the ultrasonic agitation is between about20 kHz and about 100 kHz. In some embodiments of a method of preparingan amlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 20 kHz. In some embodiments of a method of preparingan amlodipine benzoate suspension, the frequency of the ultrasonicagitation is about 40 kHz. In some embodiments of a method of preparingamlodipine benzoate, the frequency of the ultrasonic agitation ismodulated about ±1 kHz around the desired frequency.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is between about 1minute and 1 hour. In some embodiments of a method of preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes,about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes,about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes,or about 1 hour. In some embodiments of a method of preparing anamlodipine benzoate suspension, the duration of the ultrasonic agitationis between about 5 minutes and 30 minutes. In some embodiments of amethod of preparing an amlodipine benzoate suspension, the duration ofthe ultrasonic agitation is between about 5 minutes and 20 minutes. Insome embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is about 5 minutes.In some embodiments of a method of preparing an amlodipine benzoatesuspension, the duration of the ultrasonic agitation is about 10minutes.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the temperature of the first mixture or the second mixtureis not controlled.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process does not involve the use of any solvent otherthan water.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding the second mixturecomprising amlodipine benzoate to a third mixture comprising one or moreof a buffer, a preservative, a sweetening agent, a suspension agent, anantifoaming agent, water, and a flavoring agent. In some embodiments,the third mixture comprises water.

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding a second portion ofpolysorbate 80 to the second mixture comprising amlodipine benzoateprior to step (iv).

In some embodiments of a method of preparing an amlodipine benzoatesuspension, the process further comprises adding water quantum satisthereby forming the amlodipine benzoate suspension.

Methods of Treatment

Provided herein, in one aspect, are methods of treatment comprisingadministration of the amlodipine liquid formulations described herein toa subject. In some embodiments, the amlodipine liquid formulationsdescribed herein treat hypertension in a subject. Hypertension as usedherein includes both primary (essential) hypertension and secondaryhypertension. In certain instances, hypertension is classified in caseswhen blood pressure values are greater than or equal to 140/90(systolic/diastolic) mm Hg in a subject. In certain instances, theamlodipine liquid formulations described herein treat a subject having ablood pressure values are greater than or equal to 140/90 mm Hg. Incertain instances, the amlodipine liquid formulations described hereintreat primary (essential) hypertension in a subject. In other instances,the amlodipine liquid formulations described herein treat secondaryhypertension in a subject.

In other embodiments, the amlodipine liquid formulations describedherein treat prehypertension in a subject. Prehypertension as usedherein refers to cases where a subject's blood pressure is elevatedabove normal but not to the level considered to be hypertension. In someinstances, prehypertension is classified in cases when blood pressurevalues are 120-139/80-89 mm Hg. In certain instances, the amlodipineliquid formulations described herein treat a subject having bloodpressure values of 120-139/80-89 mm Hg.

In yet other embodiments, the amlodipine liquid formulations describedherein are prophylactically administered to subjects suspected ofhaving, predisposed to, or at risk of developing hypertension. In someembodiments, the administration of amlodipine liquid formulationsdescribed herein allow for early intervention prior to onset ofhypertension. In certain embodiments, upon detection of a biomarker,environmental, genetic factor, or other marker, the amlodipine liquidformulations described herein are prophylactically administered tosubjects.

In further embodiments, the amlodipine liquid formulations describedherein treat Coronary Artery Disease (CAD). In some embodiments, theamlodipine liquid formulations described herein treat chronic stableangina. In some embodiments, the amlodipine liquid formulationsdescribed herein treat vasospastic angina (Prinzmetal's or Variantangina). In some embodiments, the amlodipine liquid formulationsdescribed herein treat angiographically documented coronary arterydisease in patients without heart failure or an ejection fraction<40%.

Dosing

In one aspect, the amlodipine liquid formulations are used for thetreatment of diseases and conditions described herein. In addition, amethod for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration ofamlodipine liquid formulations in therapeutically effective amounts tosaid subject.

Dosages of amlodipine liquid formulations described can be determined byany suitable method. Maximum tolerated doses (MTD) and maximum responsedoses (MRD) for amlodipine can be determined via established animal andhuman experimental protocols as well as in the examples describedherein. For example, toxicity and therapeutic efficacy of amlodipine canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, for determining theLD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Amlodipinedosages exhibiting high therapeutic indices are of interest. The dataobtained from cell culture assays and animal studies can be used informulating a range of dosage for use in human. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED₅₀ with minimal toxicity. The dosage may vary withinthis range depending upon the dosage form employed and the route ofadministration utilized. Additional relative dosages, represented as apercent of maximal response or of maximum tolerated dose, are readilyobtained via the protocols.

In some embodiments, the amount of a given amlodipine liquid formulationthat corresponds to such an amount varies depending upon factors such asthe particular amlodipine salt or form, disease condition and itsseverity, the identity (e.g., weight, sex) of the subject or host inneed of treatment, but can nevertheless be determined according to theparticular circumstances surrounding the case, including, e.g., thespecific agent being administered, the liquid composition type, thecondition being treated, and the subject or host being treated.

In some embodiments, the amlodipine liquid formulations described hereinare provided in a dose per day from about 0.01 mg to 100 mg, from about0.1 mg to about 80 mg, from about 1 to about 60, from about 2 mg toabout 40 mg of amlodipine. In certain embodiments, the amlodipine liquidformulations described herein are provided in a daily dose of about 0.01mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6mg, about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg,about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg,about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 15 mg, about 20mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about76, mg, about 80 mg, about 85 mg, about 90 mg or about 100 mg, or anyrange derivable therein. In certain instances, the amlodipine liquidformulations described herein are provided in a dose per day of about 1mg. In certain instances, the amlodipine liquid formulations describedherein are provided in a dose per day of about 2 mg. In certaininstances, the amlodipine liquid formulations described herein areprovided in a dose per day of about 3 mg. In certain instances, theamlodipine liquid formulations described herein are provided in a doseper day of about 4 mg. In certain instances, the amlodipine liquidformulations described herein are provided in a dose per day of about 5mg. In certain instances, the amlodipine liquid formulations describedherein are provided in a dose per day of about 6 mg. In certaininstances, the amlodipine liquid formulations described herein areprovided in a dose per day of about 7 mg. In certain instances, theamlodipine liquid formulations described herein are provided in a doseper day of about 8 mg. In certain instances, the amlodipine liquidformulations described herein are provided in a dose per day of about 9mg. In certain instances, the amlodipine liquid formulations describedherein are provided in a dose per day of about 10 mg. In certaininstances, the amlodipine liquid formulations described herein areprovided in a dose per day of about 11 mg. In certain instances, theamlodipine liquid formulations described herein are provided in a doseper day of about 12 mg. The dose per day described herein can be givenonce per day or multiple times per day in the form of sub-doses givenb.i.d., t.i.d., q.i.d., or the like where the number of sub-doses equalthe dose per day.

In further embodiments, the daily dosages appropriate for the amlodipineliquid formulations described herein are from about 0.01 to about 1.0mg/kg per body weight. In one embodiment, the daily dosages appropriatefor the amlodipine liquid formulations are from about 0.02 to about 0.8mg/kg amlodipine per body weight. In another embodiment, the dailydosage appropriate for the amlodipine liquid formulations are from about0.05 to about 0.6 mg/kg per body weight. In another embodiment, thedaily dosage appropriate for the amlodipine liquid formulations is about0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about0.10 mg/kg, about 0.15 mg/kg, about 0.20 mg/kg, about 0.25 mg/kg, about0.30 mg/kg, about 0.40 mg/kg, about 0.50 mg/kg, or about 0.60 mg/kg.

In other embodiments, the amlodipine liquid formulations are provided atthe maximum tolerated dose (MTD) for amlodipine. In other embodiments,the amount of the amlodipine liquid formulations administered is fromabout 10% to about 90% of the maximum tolerated dose (MTD), from about25% to about 75% of the MTD, or about 50% of the MTD. In particularembodiments, the amount of the amlodipine liquid formulationsadministered is from about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or higher, or anyrange derivable therein, of the MTD for amlodipine.

In further embodiments, the amlodipine liquid formulations are providedin a dosage that is similar, comparable or equivalent to a dosage of aknown amlodipine tablet formulation. In other embodiments, theamlodipine liquid formulations are provided in a dosage that providessimilar, comparable or equivalent pharmacokinetic parameters (e.g., AUC,C_(max), T_(max), C_(min), T_(1/2)) as a dosage of a known amlodipinetablet formulation. Similar, comparable or equivalent pharmacokineticparameters, in some instances, refer to within 80% to 125%, 80% to 120%,85% to 125%, 90% to 110%, or increments therein, of the given values. Itshould be recognized that the ranges can, but need not be symmetrical,e.g., 85% to 105%.

Administration

Administration of an amlodipine liquid formulation is at a dosagedescribed herein or at other dose levels and formulations determined andcontemplated by a medical practitioner. In certain embodiments, theamlodipine liquid formulations described herein are administered forprophylactic and/or therapeutic treatments. In certain therapeuticapplications, the amlodipine liquid formulations are administered to apatient already suffering from a disease, e.g., hypertension, in anamount sufficient to cure the disease or at least partially arrest orameliorate the symptoms, e.g., lower blood pressure. Amounts effectivefor this use depend on the severity of the disease, previous therapy,the patient's health status, weight, and response to the amlodipineformulations, and the judgment of the treating physician.Therapeutically effective amounts are optionally determined by methodsincluding, but not limited to, a dose escalation clinical trial.

In prophylactic applications, the amlodipine liquid formulationsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, e.g., hypertension. Such anamount is defined to be a “prophylactically effective amount or dose.”In this use, the precise amounts also depend on the patient's state ofhealth, weight, and the like. When used in a patient, effective amountsfor this use will depend on the risk or susceptibility of developing theparticular disease, previous therapy, the patient's health status andresponse to the amlodipine formulations, and the judgment of thetreating physician.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of an amlodipine liquidformulations described herein are administered chronically, that is, foran extended period of time, including throughout the duration of thepatient's life in order to ameliorate or otherwise control or limit thesymptoms of the patient's disease. In other embodiments, administrationof an amlodipine liquid formulation continues until complete or partialresponse of a disease.

In certain embodiments wherein a patient's status does improve, the doseof an amlodipine liquid formulation being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). In specific embodiments, the length ofthe drug holiday is between 2 days and 1 year, including by way ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,320 days, 350 days, and 365 days. The dose reduction during a drugholiday is, by way of example only, by 10%-100%, including by way ofexample only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, and 100%.

In some embodiments, amlodipine liquid formulations described herein areadministered chronically. For example, in some embodiments, anamlodipine liquid formulation is administered as a continuous dose,i.e., administered daily to a subject. In some other embodiments,amlodipine liquid formulations described herein are administeredintermittently (e.g. drug holiday that includes a period of time inwhich the formulation is not administered or is administered in areduced amount).

In some embodiments, the amlodipine liquid formulation is administeredto a subject who is in a fasted state. A fasted state refers to asubject who has gone without food or fasted for a certain period oftime. General fasting periods include at least 4 hours, at least 6hours, at least 8 hours, at least 10 hours, at least 12 hours, at least14 hours and at least 16 hours without food. In some embodiments, anamlodipine liquid formulation is administered orally to a subject who isin a fasted state for at least 8 hours. In other embodiments, anamlodipine liquid formulation is administered to a subject who is in afasted state for at least 10 hours. In yet other embodiments, anamlodipine liquid formulation is administered to a subject who is in afasted state for at least 12 hours. In other embodiments, an amlodipineliquid formulation is administered to a subject who has fastedovernight.

In other embodiments, the amlodipine liquid formulation is administeredto a subject who is in a fed state. A fed state refers to a subject whohas taken food or has had a meal. In certain embodiments, an amlodipineliquid formulation is administered to a subject in a fed state 5 minutespost-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutespost-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutespost-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances,an amlodipine liquid formulation is administered to a subject in a fedstate 30 minutes post-meal. In other instances, an amlodipine liquidformulation is administered to a subject in a fed state 1 hourpost-meal. In yet further embodiments, an amlodipine liquid formulationis administered to a subject with food.

In further embodiments described herein, an amlodipine liquidformulation is administered at a certain time of day for the entireadministration period. For example, an amlodipine liquid formulation canbe administered at a certain time in the morning, in the evening, orprior to bed. In certain instances, an amlodipine liquid formulation isadministered in the morning. In other embodiments, an amlodipine liquidformulation can be administered at different times of the day for theentire administration period. For example, an amlodipine liquidformulation can be administered on 8:00 am in the morning for the firstday, 12 pm noon for the next day or administration, 4 pm in theafternoon for the third day or administration, and so on.

Combinations

The treatment of certain diseases or conditions (e.g., hypertension,heart failure, myocardial infarction and the like) in a subject with anamlodipine liquid formulation described herein encompass additionaltherapies and treatment regimens with other agents in some embodiments.Such additional therapies and treatment regimens can include anothertherapy, e.g., additional anti-hypertensives, for treatment of theparticular disease or condition in some embodiments. Alternatively, inother embodiments, additional therapies and treatment regimens includeother agents used to treat adjunct conditions associated with thedisease or condition or a side effect from the amlodipine liquidformulation in the therapy.

Additional agents for use in combination with an amlodipine liquidformulation described herein include, but are not limited to, diuretics(loop, thiazide, potassium-sparing, and the like), beta blockers(metoprolol, propanolol, pronethalol, and the like), alpha blockers(phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like),mixed alpha and beta blockers (bucindolol, carvedilol, labetalol),calcium channel blockers (dihydropyridines such as nifedipine, etc.,diltiazem, verapamil and the like), angiotensin II receptor antagonists(saralasin, losartan, eprosartin, irbesartan, valsartan, and the like),other ACE inhibitors (enalapril, captopril, quinapril, ramipril,lisinopril, zofenopril, and the like), aldosterone antagonists(eplerenone, spironolactone and the like), vasodilators (hydralazine andthe like) and alpha-2 agonists (clonidine, moxonidine, guanabenz and thelike).

Certain Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes the standardlevel of error for the device or method being employed to determine thevalue. The use of the term “or” in the claims is used to mean “and/or”unless explicitly indicated to refer to alternatives only or thealternatives are mutually exclusive, although the disclosure supports adefinition that refers to only alternatives and to “and/or.” The terms“comprise,” “have” and “include” are open-ended linking verbs. Any formsor tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the description includes instances where the events occurs andinstances where it does not.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In some embodiments, a therapeutic agent such asamlodipine is directed to the treatment and/or the amelioration of,reversal of, or stabilization of the symptoms of hypertension describedherein.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. Thus, as used herein, the term “administering”, when used inconjunction with an amlodipine formulation, can include, but is notlimited to, providing an amlodipine formulation into or onto the targettissue; providing an amlodipine formulation systemically to a patientby, e.g., oral administration whereby the therapeutic reaches the targettissue or cells. “Administering” a formulation may be accomplished byinjection, topical administration, and oral administration or by othermethods alone or in combination with other known techniques.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals. Asused herein, the terms “patient,” “subject” and “individual” areintended to include living organisms in which certain conditions asdescribed herein can occur. Examples include humans, monkeys, cows,sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. Ina preferred embodiment, the patient is a primate. In certainembodiments, the primate or subject is a human. In certain instances,the human is an adult. In certain instances, the human is child. Infurther instances, the human is 12 years of age or younger. In certaininstances, the human is elderly. In other instances, the human is 60years of age or older. Other examples of subjects include experimentalanimals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.The experimental animal can be an animal model for a disorder, e.g., atransgenic mouse with hypertensive pathology. A patient can be a humansuffering from hypertension, or its variants or etiological forms.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “pharmaceutical composition” shall mean a compositioncomprising at least one active ingredient, whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology). As such,a non-limiting example of a “therapeutically effective amount” or“effective amount” of a formulation of the present disclosure may beused to inhibit, block, or reverse the activation, migration, orproliferation of cells or to effectively treat hypertension orameliorate the symptoms of hypertension.

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

The terms “precipitate,” “precipitates,” or “precipitation” as usedherein, refers to the creation of a new solid phase comprising one ormore chemical entities from solution. Those of ordinary skill in the artwill understand and appreciate that the solid phase may exist incrystalline and/or amorphous forms and that crystalline forms mayinclude, but are not limited to, polymorphs, cocrystals, ioniccocrystals, ionic cocrystal solvates, salts, solvated salts andsolvates.

The terms “substantially precipitate,” “substantially precipitates” or“substantial precipitation” as used herein, refers to an amount ofprecipitation that is detectable, directly or indirectly, by techniquesknown to a person of ordinary skill in the art. Examples of techniquesmay include, but are not limited to, visual inspection of solutions todetermine changes in solution opaqueness/transparency, Focused BeamReflectance Measurement (FBRM) technology, Infrared Spectroscopy, RamanSpectroscopy, UV spectroscopy and turbidity analysis.

The terms “very slightly soluble” or “practically insoluble” as usedherein, refers to a concentration of less than about 0.6 mg/mL,preferably of less than about 0.2 mg/mL, and most preferably of lessthan about 0.05 mg/mL.

EXAMPLES Example 1: Formation of Amlodipine Salts

Amlodipine salts were prepared according to the formulas in Table 1 andTable 2. The formulations in Table 1 were prepared by adding purifiedwater to a glass container containing a magnetic stir-bar and mixingwith an external magnetic stir-plate. The polysorbate 80 was added andallowed to dissolve with mixing for a minimum of 10 minutes. Amlodipinebesylate was then added and dispersed in the solution with mixing for aminimum of 10 minutes. The salt forming agent was then added to thesuspension and the resulting suspension was mixed for an additional 30minutes. The amount of the added salt forming agent was approximately10-fold the amount of amlodipine on a mole basis. A control formulationwas prepared to provide a solubility value for amlodipine besylate.

The formulations in Table 2 were prepared by adding purified water to aglass container positioned in an ultrasonic bath. Mixing was initiatedwith an overhead mixer and impeller. The polysorbate 80 was added andallowed to dissolve with mixing for a minimum of 10 minutes. Amlodipinebesylate was then added and dispersed in the solution with mixing for aminimum of 10 minutes. The salt forming agent was then added to thesuspension along with a pH adjusting agent if needed, and ultrasonicagitation at 40 kHz was applied for 30 minutes along with overheadmixing.

An aliquot of each suspension was filtered through a 0.45 micron nylonfilter and the supernatant analyzed by an HPLC method for amlodipinecontent. The HPLC method provided separation of amlodipine from othercomponents on a C18 column with a gradient program using mobile phasescontaining 0.1% trifluoroacetic acid (TFA) in water, and 0.1% TFA inacetonitrile flowing at 1 mL/min. Detection was by UV absorbance at 237nm. The results are included in Table land Table 2.

TABLE 1 Composition of Amlodipine Salt Batches Prepared by Mixing BatchComponent (g) Control 1A 1B 1C 1D 1E 1F Purified water 500 10 10 100 10100 100 Polysorbate 80 5.0 0.10 0.10 1.0 0.10 1.0 1.0 Amlodipinebesylate 6.95 0.139 0.139 1.39 0.139 1.39 1.39(1S)-(+)-10-Camphorsulfonic — 0.568 — — — — — acid 1-Hydroxy-2-naphthoicacid — — 0.461 — — — — 1,5-Naphthalene disulfonic — — — 8.60 — — — acid,disodium Nicotinic acid, sodium — — — — 0.358 — — Pamoic acid, disodium— — — — — 10.60 — Terephthalic acid — — — — — — 4.07 Amlodipine contentin 4.80 0.63 2.44 7.11 9.04 1.70 2.26 supernatant (mg/mL)

TABLE 2 Composition of Amlodipine Salt Batches Prepared by Sonicationand Mixing Batch Component (g) 1G 1H 1I 1J 1K Purified water 100 10 10100 100 Polysorbate 80 1.0 0.10 0.10 1.0 1.0 Amlodipine besylate 1.390.139 0.139 1.39 1.39 Benzoic acid 4.24 — — — — Sodium hydroxide (5Nsolution) 8.25 — — — — (1S)-(+)-10- Camphorsulfonic acid — 0.569 — — —l-Hydroxy-2-naphthoic acid — — 0.461 — — Pamoic acid, disodium — — —10.59 — Terephthalic acid — — — — 4.07 Amlodipine content in supernatant0.73 0.63 2.58 1.42 3.84 (mg/mL)

Batches 1A-1F had different amlodipine content in the supernatants thanthe amlodipine besylate control indicating formation of new salt forms.The remaining suspension from batches 1A, 1B, 1E, and 1F (showing loweramlodipine content than amlodipine besylate) was filtered throughWhatman #1 filter paper and the solids collected, rinsed twice withpurified water, then allowed to dry at ambient conditions for one hour.Aliquots of each solid were weighed into 15 mL polypropylene centrifugetubes in duplicate except for batch 1A which was a single determination.Purified water was added to each tube and the pH of the resultingsuspension adjusted to 5.3 with anhydrous citric acid or anhydroussodium citrate powder as needed. A control was also prepared induplicate containing only purified water and amlodipine besylate at pH5.3. The tubes were capped, covered in foil to block light, and allowedto tumble end-over-end at ambient temperature for 66 hours. Thesuspensions were then filtered through 0.45 micron nylon filters and theresulting filtrates analyzed by HPLC for amlodipine content. Thecontents of each tube, and the resulting amlodipine solubilities arepresented in Table 3.

TABLE 3 Soluble Amlodipine in Isolated Solids Batch Control 1A 1B 1E 1FTube 1/2 Tube 1 Tube 1/2 Tube 1/2 Tube 1/2 Purified water (mL) 10/10 1010/10 10/10 10/10 Amlodipine besylate (mg) 49.8/53.1 — — — — Isolatedsolids added (mg) — 54.8 99.4/100.5 100.0/104.6 111.2/131.1 pH 5.38/5.265.33 5.26/5.25 5.40/5.32 5.27/5.32 Soluble amlodipine (μg/mL) 1078/1076950 0.27/0.21 0.33/0.22 9.4/5.6

Example 2: Effect of Polysorbate 80 on the Formation of AmlodipineBenzoate in Stainless Steel Containers

The benzoate salt of amlodipine was prepared in stainless steelcontainers in the absence and presence of varying amount of polysorbate80. Amlodipine besylate has been reported to adsorb/adhere to stainlesssteel surfaces with one report indicating that 0.1% polysorbate 80inhibits this adsorption/adherence in solution. The batches wereprepared using the ingredients as specified in Table 4. The batch withno polysorbate (2A) was prepared by adding the purified water to astainless steel vessel and initiating mixing with an overhead mixer andstainless steel stirrer shaft and blade. Citric acid was added anddissolved, then amlodipine besylate was added. The suspension was mixedfor ˜5 minutes then sodium benzoate was added.

Large crystals promptly formed in the suspension and solid material wasobserved to stick to, and coat, the stir-shaft and impeller as well asthe inner surface of the stainless steel vessel. No further processingor sampling was undertaken.

The polysorbate containing batches (2B-2F) were prepared as 7.5%concentrates by adding 4.50 liters of purified water to a stainlesssteel sonication tank with an overhead mixer and stainless steel stirrershaft and blade. Mixing was initiated and the polysorbate 80 was added.The polysorbate container was rinsed with 0.25 L purified water and therinse was added to the tank. The solution was stirred for 10 minutes andthe amlodipine besylate was added to the tank. The amlodipine besylatecontainer was rinsed with 0.25 L purified water and the rinse was addedto the tank. The solution/suspension was stirred for 10 minutes thensonication was initiated (40 kHz frequency, 280 watts) and sodiumbenzoate was added to the tank. The sonication was discontinued after 10minutes and the mixing continued for an additional 20 minutes. No solidmaterial was observed to adhere to the container or the mixing shaft andblade. Samples of the suspension were taken periodically, filteredthrough a 0.45 micron nylon filter and the supernatant analyzed by theHPLC method in Example 1 for amlodipine content. Additional samples ofthe suspension were taken after the sonication and subsequent 20 minutestirring were completed. The samples were evaluated for particle sizewith a Malvern Mastersizer S using a 5 mg/mL sodium benzoate in waterdispersant.

TABLE 4 Amlodipine Salt Batches Evaluating Polysorbate Content Batch 2A2B 2C 2D 2E 2F Components (grams) Purified water 1350 5000 5000 50005000 5000 Citric acid, anhydrous 0.825 — — — — — Polysorbate 80 0 5.0015.0 25.0 30.0 66.7 Amlodipine besylate 2.08 92.6 92.6 92.6 92.6 92.6Sodium benzoate 7.50 333.6 333.6 333.6 333.6 333.6 Results Particle size(μm) D10 — 5 3 3 3 3 D50 — 29 13 14 13 14 D90 — 56 32 43 34 33

The concentration of amlodipine in solution over time for batches 2B-2Fare given in FIG. 1 .

Example 3: Effect of Sonication on the Formation of Amlodipine Benzoate

The benzoate salt of amlodipine was prepared with overhead stirring(Formulation 3A), magnetic stir-bar stirring (Formulation 3B), and bysonication (40 kHz) with overhead stirring (Formulation 3C). Theresulting suspensions were then used to prepare sweetened, suspended,formulations. The compositions of the three formulations are given inTable 5.

TABLE 5 Amlodipine Formulations Prepared by Different Mixing MethodsFormulation Salt Formation Step (grams) 3A 3B 3C Purified water-I 300100 5000 Polysorbate 80 3.00 1.00 50.0 Amlodipine besylate 4.17 1.3969.5 Sodium benzoate 15.0 5.00 250.0 Formulation Step (grams) Purifiedwater-II 2433 812 487 Citric acid, anhydrous 0.93 0.310 0.186 Sodiumcitrate, anhydrous 1.08 0.361 0.216 Simethicone 30% w/w powder 1.50 0.500.300 Sucralose 2.10 0.70 0.420 Colloidal silicon dioxide 1.50 0.50 0.30Hypromellose 22.5 7.50 4.50 Purified water III q.s. 3L q.s. IL q.s. 0.6LResults Particle size (μm) D10 16 12 3 D50 46 32 13 D90 194 96 29

The amlodipine salts were prepared by adding the Purified water-I to astainless steel vessel (Formulations 3A, 3B), or sonication tank(Formulation 3C). Mixing was initiated and the polysorbate 80, thenamlodipine besylate, was added with 5 minutes of mixing following eachaddition. The sodium benzoate was added, and sonication was initiatedfor Formulation 3C. Mixing was continued for 30 minutes after the sodiumbenzoate addition for all batches, and sonication for 3C was continuedfor 10 minutes after the sodium benzoate addition.

Purified water II was added to a glass vessel for each of theformulations and magnetic stir bar mixing was initiated for each. Thefollowing ingredients were added to each vessel with 5 minutes of mixingbetween each addition; citric acid, sodium citrate, simethicone 30%solid (NuSil Med-342P), sucralose, colloidal silicon dioxide (Cab-O-SilM-5P), and hypromellose (Benecel K1500). The magnetic stir bar wasremoved, and high shear mixing was applied for 2 minutes to disperse andhydrate the hypromellose. The full contents of the suspension from thesalt formation step for Formulations 3A and 3B and 64.3 grams of thesuspension from Formulation 3C (containing the salt equivalent of 0.832g amlodipine besylate) were added to the glass vessels and high shearmixing was applied for 1 minute to disperse the amlodipine benzoateparticles. The formulations were brought to their respective finalvolume with Purified water III, and mixed until uniform.

Samples of each suspension were taken and evaluated for particle sizewith a Malvern Mastersizer S using a 5 mg/mL sodium benzoate in waterdispersant. The results are presented in Table 5.

Example 4: Effect of Sonication Frequency on the Formation of AmlodipineBenzoate

A batch of amlodipine benzoate salt (4A) was prepared containing thesame composition as batch 2F. The preparation procedure was the same asfor batch 2F with the exception that the sonication frequency was 20kHz. Samples of the suspension were taken periodically, filtered througha 0.45 micron nylon filter and the supernatant analyzed by the HPLCmethod in Example 1 for amlodipine content. Additional samples of thesuspension were taken after the sonication and subsequent 20 minutestirring, and the samples were evaluated for particle size with aMalvern Mastersizer S using a 5 mg/mL sodium benzoate in waterdispersant. The measured particle size of batch 4A was D10=4 micron,D50=19 micron, and D90=55 micron and the particle size of batch 2F wasD10=3 micron, D50=14 micron, and D90=33 micron. The concentration ofsoluble amlodipine in solution over time for batches 2F and 4A are givenin FIG. 2 .

Example 5: Effect of Sonication Duration on the Formation of AmlodipineBenzoate

Batches of amlodipine benzoate salt were prepared containing thecomponents as shown in Table 6. The batches were prepared according tothe procedure used for the preparation of batch 2F with the exceptionthat the sonication was conducted for 10 minutes for batch 5A and for 30minutes for batch 5B. Samples of each suspension were taken periodicallyduring the procedure, filtered through a 0.45 micron nylon filter andthe supernatant analyzed by the HPLC method in Example 1 for amlodipinecontent. The concentration of soluble amlodipine in solution over timefor batches 5A and 5B was essentially the same.

TABLE 6 Amlodipine Salt Batches Evaluating Sonication Duration BatchComponents (grams) 5A 5B Purified water 5000 5000 Polysorbate 80 50.050.0 Amlodipine besylate 69.5 69.5 Sodium benzoate 50.0 50.0 Sonicationduration 10 min 30 min

Example 6: Effect of Solution Concentration on the Formation ofAmlodipine Benzoate

Amlodipine benzoate salt was prepared under conditions where theconcentrations of ingredients was varied to simulate preparation of thesalt under various concentrate conditions. The compositions of thebatches are given in Table 7 along with batches 2F and 3C. The batcheswere prepared according to the procedure used for batch 2F. Samples ofthe suspension from batch 6B was taken and evaluated for particle sizewith a Malvern Mastersizer S using a 5 mg/mL sodium benzoate in waterdispersant.

TABLE 7 Composition and Particle Sizes of Amlodipine Salt Batches Madeas Concentrates Batch Component (grams) 6A 2F 3C 6B Purified water 50005000 5000 5000 Polysorbate 80 100.0 66.7 50.00 5.00 Amlodipine besylate139.0 92.6 69.5 6.95 Sodium benzoate 500.0 333.3 250.0 25.0Condition/Result Concentrate volume % 5 7.5 10 100 Particle size (μm)D10 — 3 3 8 D50 — 14 13 30 D90 — 33 29 72

Example 7: Amlodipine Salt Formation when Varying the PolysorbateAddition

Amlodipine salts were prepared as 10% concentrates containing thecompositions shown in Table 8. Batch 7A was prepared by adding 41 kgpurified water to a 22 gallon sonication tank with an overhead mixer andstainless steel stirrer shaft and blade. Mixing was initiated andpolysorbate 80 [Aliquot 1] was added. The polysorbate container wasrinsed with 0.5 L purified water and the rinse was added to the tank.The solution was stirred for 10 minutes and the amlodipine besylate wasadded to the tank. The amlodipine besylate container was rinsed with 0.5L purified water and the rinse was added to the tank. Thesolution/suspension was stirred for 10 minutes then sonication wasinitiated (40 kHz frequency with ±1 kHz modulation, 1500 watts) andsodium benzoate was added to the tank. The sonication was discontinuedafter 10 minutes. Mixing continued for an additional 20 minutes afterthe sonication was discontinued, then polysorbate 80 [Aliquot 2] wasadded. The polysorbate container was rinsed with 0.5 L purified waterand the rinse was added to the tank. The suspension was mixed for anadditional 10 minutes.

Batch 7B was prepared by adding 290 g purified water to a 600 mL glassbeaker mounted in a sonication tank. An overhead mixer with a PTFEstirrer shaft and blade was positioned to mix the solution in the beakerMixing was initiated and polysorbate 80 [Aliquot 1] was added. Thepolysorbate container was rinsed with 5 mL purified water and the rinsewas added to the beaker. The solution was stirred for 10 minutes and theamlodipine besylate was added to the beaker. The amlodipine besylatecontainer was rinsed with 5 mL purified water and the rinse was added tothe beaker. The solution/suspension was stirred for 10 minutes thensonication was initiated (40 kHz frequency, 280 watts) and sodium2-napthalene sulfonate was added to the beaker. The sonication wasdiscontinued after 10 minutes and the mixing was continued for anadditional 20 minutes.

TABLE 8 Composition of Amlodipine Salt Batches Varying PolysorbateAddition Batch Component (grams) 7A 7B Purified water 42500 300Polysorbate 80 [Aliquot 1] 255.0 0.30 Amlodipine besylate 591 4.16Sodium benzoate 2125 — Sodium 2-napthalene sulfonate — 3.39 Polysorbate80 [Aliquot 2] 170.0 —

Example 8: Stability of Amlodipine Formulations

Formulations were prepared containing Amlodipine according to thecompositions in Table 9, using the amlodipine salts prepared in Example7. Each formulation contained amlodipine equivalent to 1.39 mg/mL ofamlodipine besylate.

Formulations 8A-C were prepared by adding the ingredients to a volume ofpurified water that was about 80% of the final volume of theformulation. The suspending agent, hypromellose or xanthan gum, wasadded last and high shear mixing was applied to disperse and hydrate thesuspending agent. The appropriate amount of batch 7A was added to eachand the formulations were brought to their final volume with purifiedwater. The pH of each formulation was measured.

Formulation 8D was prepared by heating to 75° C., a volume of purifiedwater that was about 50% of the final volume of the formulation. Themagnesium aluminum silicate was added and mixed for 45 minutes. Thesucrose and sorbitol were added to the hot suspension and dissolved. Theformulation was then cooled to ambient temperature and the sodiumcitrate, simethicone, microcrystalline cellulose, and 0.31 mg/mL citricacid were added. The appropriate amount of batch 7A was added and theformulation was brought to final volume with purified water. The pH wasmeasured and adjusted to 5.3 with additional citric acid.

Formulations 8E was prepared using purified water in an amount that wasabout 65% the final volume of the formulation. The Carbopol was addedand dissolved, followed by citric acid, sodium citrate (0.36 mg/mL),xylitol, simethicone and silicon dioxide. The appropriate amount ofbatch 7A was added and the formulation was brought to final volume withpurified water. The pH was measured and adjusted to 5.3 with additionalsodium citrate.

Formulation 8F was prepared using purified water in an amount that wasabout 40% of the final volume of the formulation. Citric acid (0.31mg/mL), sodium citrate, sucralose, maltitol, simethicone andmicrocrystalline cellulose were added. Methylcellulose was then addedand high shear mixing applied to disperse and hydrate the cellulose. Thesuspension was then mixed for 15 minutes to allow for dissipation ofentrapped air. The appropriate amount of batch 7A was added and theformulation was brought to final volume with purified water. The pH wasmeasured and adjusted to 5.3 with additional citric acid.

Formulation 8G was prepared by dissolving 0.27 g polysorbate 80 in 240 gpurified water with mixing in a beaker. The polysorbate container wasrinsed with 5 mL water and the rinse was added to the beaker. Thefollowing ingredients were then added individually with mixing; citricacid, sodium citrate, sodium benzoate, sucralose, simethicone andcolloidal silicon dioxide. Hypromellose was then added and thesuspension was subjected to high shear mixing to disperse and hydratethe hypromellose. A 30.78 gram aliquot of batch 7B was added to thebeaker and additional purified water was added to bring the formulationto a final volume of 300 mL. The formulation was mixed well.

Each formulation was dispensed into screw-capped high densitypolyethylene (HDPE) bottles and stored at both 5±5° C. and 25±5° C. forformulations 8A-8F and at both 25° C. and 40±5° C. for formulation 8G.Samples were removed periodically and analyzed by a stability indicatinghigh performance liquid chromatography (HPLC) method for content ofamlodipine and any degradants.

The HPLC method provided separation of amlodipine, amlodipine degradantsand formulation components on a C18 column with a gradient program usingmobile phases containing 0.1% trifluoroacetic acid (TFA) in water, and0.1% TFA in acetonitrile flowing at 1 mL/min. Detection was by UVabsorbance at 237 nm for amlodipine and its degradants. Any unknownimpurities were reported by their relative retention time (RRT) toamlodipine.

TABLE 9 Composition of Amlodipine Formulations for Stability AssessmentFormulation Component 8A 8B 8C 8D 8E 8F 8G Amlodipine^(a) 1.00 1.00 1.001.00 1.00 1.00 1.00 Polysorbate 80 1.00 1.00 1.00 1.00 1.00 1.00 1.00Sodium benzoate 5.00 5.00 5.00 5.00 5.00 5.00 1.00 Sodium 2-napthalenesulfonate — — — — — — 1.13 Acetic acid 0.26 — — — — — — Citric acid,anhydrous — 0.31 0.31 0.63 0.31 0.39 0.31 Sodium citrate, anhydrous —0.42 0.42 0.36 5.95 0.36 0.42 Sucralose 0.70 0.70 0.70 — — 0.50 0.70Maltitol syrup — — — — — 400    — (Lycasin 80/55) Sorbitol — — — 100   — — — Xylitol — — — — 150    — — Sucrose — — — 630    — — — Simethicone30% w/w powder 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Colloidal silicondioxide 0.50 0.50 0.50 — 0.50 0.50 Microcrystalline cellulose (Avicel —— — 6.0  — 5.0  — PH101) Hypromellose 7.5  7.5  — — — — 7.5  (BenecelK1500) Xanthan gum — — 1.5 — — — — Magnesium aluminum silicate — — —15    — — — (Veegum) Carbopol 971P — — — — 3.0  — — Methylcellulose — —— — — 10.0  — (Methocel A15C) Purified water q.s. q.s. q.s. q.s. q.s.q.s. q.s. pH 5.3  5.4  5.4  5.3  5.3  5.3  5.1  ^(a)= equivalent to 1.39mg/ml Amlodipine besylate

Initial HPLC analysis for amlodipine and the main degradants in thesamples (8A-8G) stored at 5±5° C. suggest that one or more of theformulations are stable.

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 5±5° C. are provided in Table 10. When storedat 5±5° C., Sample 8G is contemplated to have similar or betterstability compared to samples 8A-8F.

TABLE 10 Assay and Primary Degradants Present in the FormulationsFormulation 8A 8B 8C 8D 8E 8F Weeks Amlodipine (% initial) Initial 100.0100.0 100.0 100.0* 100.0 100.0 4 99.1 99.9 94.4 111.8* 99.5 100.1 8 98.3100.1 99.8 162.0* 99.8 99.7 12 98.8 100.1 100.1 213.8* 101.1 100.2 2698.6 100.0 100.3 193.2* 100.3 97.9 52 97.5 99.6 100.0 99.0 99.7 WeeksTotal Impurities (wt % of Amlodipine) Initial 0.13 0.06 0.05 0.27* 0.180.15 4 0.28 0.12 0.08 0.35* 0.27 0.08 8 0.51 0.17 0.11 0.13* 0.19 0.0812 0.70 0.20 0.14 0.22* 0.25 0.10 26 0.93 0.29 0.18 0.20* 0.33 0.08 521.18 0.46 0.24 0.66 0.42 *Formulation 8D was incompatible with the HPLCcolumn, and thus the amlodipine and impurity contents cannot be measuredusing the HPLC method.

The results of the HPLC analysis for amlodipine and the main degradantsin the samples stored at 25±5° C. and 40±5° C. (8G) are provided inTable 11.

TABLE 11 Assay and Primary Degradants Present in the FormulationsFormulation 8A 8B 8C 8D 8E 8F 8G 8G (25° C.) (25° C.) (25° C.) (25° C.)(25° C.) (25° C.) (25° C.) (40° C.) Weeks Amlodipine (% initial) Initial100.0  100.0  100.0 100.0* 100.0  100.0  100.0 100.0  4 97.0 99.7 100.0105.3* 95.9 98.5 98.3 97.3 8 96.8 98.9 97.9 119.6* 95.3 97.2 99.6 96.612 96.1 98.4 98.0 183.2* 93.5 97.1 99.9 94.7 26 93.6 96.0 95.4 174.7*88.0 93.6 102.3 86.6 52 — — — — — — 100.2 — Weeks Total Impurities (wt %of Amlodipine) Initial 0.13 0.06 0.05 0.27* 0.18 0.15 0.23 0.23 4 0.740.42 0.35 0.36* 1.18 0.31 0.33 0.43 8 1.27 0.84 0.64 0.12* 1.42 0.610.20 1.56 12 1.69 1.30 0.99 0.26* 1.93 0.55 0.23 1.99 26 2.99 2.39 2.000.27* 3.87 1.37 0.31 3.61 52 — — — — — — 0.56 — *Formulation 8D wasincompatible with the HPLC column, and thus the amlodipine and impuritycontents cannot be measured using the HPLC method.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A particle suspension comprising amlodipinebenzoate and having a median particle diameter D50 value of between 5 μmand 40 μm, wherein the suspension is made by mixing amlodipine besylateand sodium benzoate in an aqueous solution, thereby forming the particlesuspension comprising amlodipine benzoate.
 2. The suspension of claim 1,wherein the particle D50 value is between 10 μm and 20 μm.
 3. Thesuspension of claim 1, wherein the particles have a D90 value between 20μm and 60 μm, and wherein the D90 value refers to a particle diameter,wherein 10% of the volume of the sampled particles have a diameter largethan, and 90% of the volume of the sample particles have a diametersmaller than the D90 value.
 4. The suspension of claim 1, wherein theconcentration of amlodipine besylate is between about 12 mg/ml and about20 mg/ml.
 5. The suspension of claim 1, wherein the concentration ofsodium benzoate is between about 40 mg/ml and about 70 mg/ml.
 6. Thesuspension of claim 1, wherein the mixing comprises ultrasonicagitation.
 7. The suspension of claim 6, wherein the ultrasonicagitation has a frequency of between about 20 kHz and about 100 kHz. 8.The suspension of claim 1, wherein the mixing occurs by a mixing device,wherein the mixing device is a homogenizer or a blender.
 9. Thesuspension of claim 1, wherein the duration of the mixing is betweenabout 1 minute and about 1 hour.
 10. The suspension of claim 9, whereinthe duration of the mixing is between about 1 minute and about 30minutes.
 11. The suspension of claim 1, wherein the final concentrationof amlodipine benzoate in the suspension is equivalent to about 1.0mg/ml of amlodipine free base.
 12. The suspension of claim 1, whereinthe suspension further comprises at least one buffer, a preservative, asweetening agent, a suspension agent, an antifoaming agent, and aflavoring agent.
 13. The suspension of claim 12, wherein the suspensionagent comprises silicon dioxide, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, xanthangum, magnesium aluminum silicate, crosslinked polyacrylic acid polymers,or any combination thereof.
 14. The suspension of claim 12, wherein thesuspension agent is a combination of silicon dioxide and hydroxypropylmethylcellulose.
 15. The suspension of claim 12, wherein the amount ofpreservative is about 0.1 mg/ml to about 5.0 mg/ml.
 16. The suspensionof claim 12, wherein the buffer comprises a citrate buffer.
 17. Thesuspension of claim 16, wherein the citrate buffer is about 3 mM. 18.The suspension of claim 12, wherein the antifoaming agent issimethicone.
 19. The suspension of claim 1, wherein the suspension isstable at about 25±5° C. for at least 6 months.
 20. The suspension ofclaim 1, wherein the suspension is stable at about 5±5° C. for at least6 months.